325 results on '"Maurizio C. Capogrossi"'
Search Results
2. Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells
- Author
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Sara Beji, Marco D’Agostino, Elisa Gambini, Sara Sileno, Alessandro Scopece, Maria Cristina Vinci, Giuseppina Milano, Guido Melillo, Monica Napolitano, Giulio Pompilio, Maurizio C. Capogrossi, Daniele Avitabile, and Alessandra Magenta
- Subjects
Doxorubicin ,Anthracyclines ,Ultraviolet radiation ,Alarmin ,Cardiotoxicity ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM on hCmPCs. Results We found that following the double-strand break formation in hCmPCs caused by Dox, NPM was rapidly secreted in the extracellular space by an active mechanism, in the absence of either apoptosis or necrosis. Extracellular release of NPM was similarly seen in response to ultraviolet radiation (UV). Furthermore, we observed an increase of NPM levels in the plasma of Dox-treated mice; thus, NPM release also occurred in vivo. The treatment of hCmPCs with extracellular recombinant NPM induced a decrease of cell proliferation and a response mediated through the Toll-like receptor (TLR)4. We demonstrated that NPM binds to TLR4, and via TLR4, and nuclear factor kappa B (NFkB) activation/nuclear translocation, exerts proinflammatory functions by inducing IL-6 and COX-2 gene expression. Finally, we found that in hCmPCs, NPM secretion could be driven by an autophagy-dependent unconventional mechanism that requires TLR4, since TLR4 inhibition dramatically reduced Dox-induced secretion. Conclusions We hypothesise that the extracellular release of NPM could be a general response to DNA damage since it can be elicited by either a chemical agent such as Dox or a physical genotoxic stressor such as UV radiation. Following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and a TLR4/NFκB-dependent inflammatory response.
- Published
- 2021
- Full Text
- View/download PDF
3. MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo
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Luisa de Latouliere, Isabella Manni, Laura Ferrari, Federica Pisati, Maria Grazia Totaro, Aymone Gurtner, Emanuele Marra, Lucrezia Pacello, Ombretta Pozzoli, Luigi Aurisicchio, Maurizio C. Capogrossi, Gianluca Deflorian, and Giulia Piaggio
- Subjects
Medicine ,Science - Abstract
Abstract We developed a novel reporter transgenic zebrafish model called MITO-Luc/GFP zebrafish in which GFP and luciferase expression are under the control of the master regulator of proliferation NF-Y. In MITO-Luc/GFP zebrafish it is possible to visualize cell proliferation in vivo by fluorescence and bioluminescence. In this animal model, GFP and luciferase expression occur in early living embryos, becoming tissue specific in juvenile and adult zebrafish. By in vitro and ex vivo experiments we demonstrate that luciferase activity in adult animals occurs in intestine, kidney and gonads, where detectable proliferating cells are located. Further, by time lapse experiments in live embryos, we observed a wave of GFP positive cells following fin clip. In adult zebrafish, in addition to a bright bioluminescence signal on the regenerating tail, an early unexpected signal coming from the kidney occurs indicating not only a fin cell proliferation, but also a systemic response to tissue damage. Finally, we observed that luciferase activity was inhibited by anti-proliferative interventions, i.e. 5FU, cell cycle inhibitors and X-Rays. In conclusion, MITO-Luc/GFP zebrafish is a novel animal model that may be crucial to assess the spatial and temporal evolution of cell proliferation in vivo.
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- 2021
- Full Text
- View/download PDF
4. Extracellular Nucleophosmin Is Increased in Psoriasis and Correlates With the Determinants of Cardiovascular Diseases
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Marco D'Agostino, Sara Beji, Sara Sileno, Daniela Lulli, Laura Mercurio, Stefania Madonna, Corrado Cirielli, Sabatino Pallotta, Cristina Albanesi, Maurizio C. Capogrossi, Daniele Avitabile, Guido Melillo, and Alessandra Magenta
- Subjects
alarmin ,inflammation ,microRNAs ,psoriasis ,atherosclerosis ,cardiovascular diseases ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
We previously showed that genotoxic stress induced an active extracellular release of nucleophosmin (NPM) in human cardiac mesenchymal progenitor cells, and that serum deprivation provokes NPM secretion from human endothelial cells, eliciting inflammation via nuclear factor kappa B (NF-kB) transcriptional activation. In this study, we wanted to determine whether NPM was similarly modulated in the skin and plasma of psoriatic patients (Pso). We found that NPM was induced in 6 skin biopsies compared to 6 normal skin biopsies and was markedly increased in lesional (LS) vs. non-lesional skin (NLS) biopsies. Moreover, NPM was also increased at the transcriptional levels in LS vs. NLS. Both the innate stimuli, such as lipopolysaccharides and Poly inositol–cytosine and adaptive stimuli, that is, cytokine mix, were able to induce the extracellular release of NPM in immortalized keratinocytes and human skin fibroblasts in the absence of cytotoxicity. Interestingly, NPM interacts with Toll-like receptor (TLR)4 in these cells and activates an NF-kB-dependent inflammatory pathway upregulating interleukin IL-6 and COX-2 gene expression. Finally, circulating NPM was increased in the plasma of 29 Pso compared to 29 healthy controls, and positively correlates with psoriasis area severity index (PASI) and with determinants of cardiovascular diseases (CVDs), such as pulse wave velocity, systolic pressure, and left ventricular mass. Furthermore, NPM positively correlates with miR-200c circulating levels, which we previously showed to increase in Pso and correlate with CVD progression. Our data show that circulating miR-200c is physically associated with extracellular NPM, which most probably is responsible for its extracellular release and protection upon cytokine mix via a TLR4-mechanism. In conclusion, NPM is increased in psoriasis both in the skin and plasma and might be considered a novel biologic target to counteract chronic inflammation associated with CVD risk.
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- 2022
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- View/download PDF
5. Platelet-Derived Growth Factor-Receptor α Strongly Inhibits Melanoma Growth In Vitro and In Vivo
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Debora Faraone, Maria Simona Aguzzi, Gabriele Toietta, Angelo M. Facchiano, Francesco Facchiano, Alessandra Magenta, Fabio Martelli, Silvia Truffa, Eleonora Cesareo, Domenico Ribatti, Maurizio C. Capogrossi, and Antonio Facchiano
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. The expression of platelet-derived growth factor receptors (PDGF-Rs) is reported to be reduced in metastatic melanoma compared with benign nevi or normal skin; we then hypothesized that PDGF-Rα may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Rα respond to serum with a significantly lower proliferation compared with that of controls. Apoptosis, cell cycle arrest, pRb dephosphorylation, and DNA synthesis inhibition were also observed in cells overexpressing PDGF-Rα. Proliferation was rescued by PDGF-Rα inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Rα mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Rα was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Rα show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Bα and a marked increase of p38γ, mitogen-activated protein kinase kinase 3, and signal regulatory protein α1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Rα reached a significant 70% inhibition of primary melanoma growth (P < .001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-Rα strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.
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- 2009
- Full Text
- View/download PDF
6. Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue
- Author
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Giuliana Di Rocco, Antonietta Gentile, Annalisa Antonini, Silvia Truffa, Giulia Piaggio, Maurizio C. Capogrossi, and Gabriele Toietta Ph.D.
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Medicine - Abstract
Presently, orthotopic liver transplant is the major therapeutic option for patients affected by primary liver diseases. This procedure is characterized by major invasive surgery, scarcity of donor organs, high costs, and lifelong immunosuppressive treatment. Transplant of hepatic precursor cells represents an attractive alternative. These cells could be used either for allogeneic transplantation or for autologous transplant after ex vivo genetic modification. We used stromal cells isolated from adipose tissue (AT-SCs) as platforms for autologous cell-mediated gene therapy. AT-SCs were transduced with lentiviral vectors expressing firefly luciferase, allowing for transplanted cell tracking by bioluminescent imaging (BLI). As a complementary approach, we followed circulating human α1-antitrypsin (hAAT) levels after infusion of AT-SCs overexpressing hAAT. Cells were transplanted into syngeneic mice after CCl 4 -induced hepatic injury. Luciferase bioluminescence signals and serum hAAT levels were measured at different time points after transplantation and demonstrate persistence of transplanted cells for up to 2 months after administration. These data, along with immunohistochemical analysis, suggest engraftment and repopulation of injured livers by transplanted AT-SCs. Moreover, by transcriptional targeting using cellular tissue-specific regulatory sequences, we confirmed that AT-SCs differentiate towards a hepatogenic-like phenotype in vitro and in vivo. Additionally, in transplanted cells reisolated from recipient animals' livers, we detected activation of the α-fetoprotein (AFP) promoter. This promoter is normally transcriptionally silenced in adult tissues but can be reactivated during liver regeneration, suggesting commitment towards hepatogenic-like differentiation of engrafted cells in vivo. Our data support AT-SC-mediated gene therapy as an innovative therapeutic option for disorders of liver metabolism.
- Published
- 2012
- Full Text
- View/download PDF
7. Enhanced Healing of Diabetic Wounds by Topical Administration of Adipose Tissue-Derived Stromal Cells Overexpressing Stromal-Derived Factor-1: Biodistribution and Engraftment Analysis by Bioluminescent Imaging
- Author
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Giuliana Di Rocco, Antonietta Gentile, Annalisa Antonini, Francesca Ceradini, Joseph C. Wu, Maurizio C. Capogrossi, and Gabriele Toietta
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Internal medicine ,RC31-1245 - Abstract
Chronic ulcers represent a major health problem in diabetic patients resulting in pain and discomfort. Conventional therapy does not guarantee adequate wound repair. In diabetes, impaired healing is partly due to poor endothelial progenitor cells mobilisation and homing, with altered levels of the chemokine stromal-derived factor-1 (SDF-1) at the wound site. Adipose tissue-associated stromal cells (AT-SCs) can provide an accessible source of progenitor cells secreting proangiogenic factors and differentiating into endothelial-like cells. We demonstrated that topical administration of AT-SCs genetically modified ex vivo to overexpress SDF-1, promotes wound healing into diabetic mice. In particular, by in vivo bioluminescent imaging analysis, we monitored biodistribution and survival after transplantation of luciferase-expressing cells. In conclusion, this study indicates the therapeutic potential of AT-SCs administration in wound healing, through cell differentiation, enhanced cellular recruitment at the wound site, and paracrine effects associated with local growth-factors production.
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- 2011
- Full Text
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8. Contributors
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Ahmed Safwat Abouhashem, Aamir Ahmad, Shazia Ahmad, Saira R. Ali, Tyler Anderson, Daniele Avitabile, Asha Balakrishnan, Mumtaz Yaseen Balkhi, Bin Bao, Nasma Bastaki, Christophe Beclin, Soumaya Ben-Aicha, Andreas Bosio, Emily Bruch, George A. Calin, Yang Cao, Maurizio C. Capogrossi, Andrea Caporali, Derryn Xin Hui Chan, Yuk Cheung Chan, Pavithra L. Chavali, Sreenivas Chavali, Alex F. Chen, Xiaona Chen, Charles Cook, Harold Cremer, Catherine Czeisler, Duaa Dakhlallah, Amitava Das, Anne M. Delany, Dasa Dolezalova, Juan Domínguez-Bendala, Manar A. EI Naggar, Costanza Emanueli, Michael Ezzie, Sara T. Fathallah, Tiziana Franceschetti, Roberto Gambari, Subhadip Ghatak, Jonathan M. Gleadle, Le Luo Guan, Denis C. Guttridge, Patrick Edwin Gygli, Khawaja H. Haider, Aleš Hampl, Sen Han, Martin C. Harmsen, Yoshinori Hasegawa, Sara A. Hashish, Eric Hesse, John D. Houlé, Kazuki Inoue, Jared Jagdeo, Imran Khan, Mahmood Khan, Shirin Elizabeth Khorsandi, Dagmar Klein, Dejuan Kong, Guido Krenning, Praveen Kusumanchi, Yiwei Li, Zhigang Li, Suthat Liangpunsakul, Kenneth W. Liechty, Amanda Louiselle, Leina Lu, Alessandra Magenta, Nilusha Malmuthuge, Andrew Mamalis, Clay B. Marsh, Selina Möbus, Ganesh Mohan, Peter J. Mohler, Leni Moldovan, Paloma del C. Monroig, Marek Mraz, S. Patrick Nana-Sinkam, Colby R. Neumann, Stephen Niemiec, José Javier Otero, Durba Pal, Ricardo L. Pastori, Melissa G. Piper, Giulio Pompilio, Mirza Muhammed Fahd Qadir, Srinivas Ramsamy, Darling Rojas-Canales, Alessandra Rossini, Sashwati Roy, Yashika Rustagi, Alaa A. Salama, Mohamed Salama, Prabha Sampath, Fazlul H. Sarkar, Mitsuo Sato, Chandan K. Sen, David S. Shames, Amar Deep Sharma, Anjali Kumari Singh, Kanhaiya Singh, Mithun Sinha, Prashant Srivastava, Hao Sun, Yeqing Sun, Hidetoshi Tahara, Hanna Taipaleenmäki, Joanne Trgovich, Elise J. Tucker, Huating Wang, Jie-Mei Wang, Lijun Wang, Yijie Wang, Brandon Watson, Dan Xu, Junwang Xu, Yi Xuan, Dakai Yang, Zhihong Yang, Nouran Yonis, Marina E. Zambrotta, Carlos Zgheib, Ting Zhang, Baohong Zhao, Yu Zhao, and Liang Zhou
- Published
- 2023
9. miRNA in Cardiac Regeneration
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Alessandra Magenta, Daniele Avitabile, Alessandra Rossini, Giulio Pompilio, and Maurizio C. Capogrossi
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- 2023
10. Regression of Human Breast Carcinoma in Nude Mice after Adsflt Gene Therapy Is Mediated by Tumor Vascular Endothelial Cell Apoptosis
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Judith Mühlhauser, Antonella Mangoni, Dieter Marmé, Donald P. Bottaro, Petra Reusch, Young H. Lee, Maurizio C. Capogrossi, Imre Kovesdi, Dinuka M. De Silva, and Angelina Felici
- Subjects
Cancer Research ,Endothelium ,business.industry ,Genetic enhancement ,Cancer ,medicine.disease ,Vascular endothelial growth factor ,chemistry.chemical_compound ,soluble FLT-1 ,breast carcinoma ,vessel regression ,adenovirus ,gene therapy ,medicine.anatomical_structure ,Oncology ,chemistry ,Apoptosis ,Fibrosis ,In vivo ,embryonic structures ,Cancer research ,medicine ,business ,Receptor - Abstract
Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks tumors were injected either with Adsflt, or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) was decreased by 91% relative to that of the negative control group (388 ± 94 mm3; Psflt-infected tumors exhibited complete regression. The vascular density in Adsflt-infected tumors was reduced by 50% relative to that of negative controls (Psflt–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsflt intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects.
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- 2022
- Full Text
- View/download PDF
11. Regression of Human Breast Carcinoma in Nude Mice after Ad
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Angelina, Felici, Donald P, Bottaro, Antonella, Mangoni, Petra, Reusch, Dieter, Marmé, Imre, Kovesdi, Dinuka M, De Silva, Young H, Lee, Maurizio C, Capogrossi, and Judith, Mühlhauser
- Abstract
Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Ad
- Published
- 2022
12. Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells
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Giuseppina Milano, Maurizio C. Capogrossi, Alessandro Scopece, Giulio Pompilio, Sara Beji, Monica Napolitano, Maria Cristina Vinci, Sara Sileno, Marco D'Agostino, Daniele Avitabile, Alessandra Magenta, Elisa Gambini, and Guido Melillo
- Subjects
Ultraviolet radiation ,Cell cycle checkpoint ,QH301-705.5 ,Ultraviolet Rays ,Physiology ,DNA damage ,Cell ,Apoptosis ,Plant Science ,030204 cardiovascular system & hematology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Paracrine Communication ,medicine ,Extracellular ,Alarmins ,Animals ,Humans ,Anthracyclines ,Secretion ,Biology (General) ,Progenitor cell ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0303 health sciences ,integumentary system ,Cell growth ,NF-kappa B ,Nuclear Proteins ,Heart ,Mesenchymal Stem Cells ,Cell Biology ,Cardiotoxicity ,Cell biology ,Toll-Like Receptor 4 ,Autocrine Communication ,medicine.anatomical_structure ,Alarmin ,Doxorubicin ,General Agricultural and Biological Sciences ,Nucleophosmin ,Research Article ,Developmental Biology ,Biotechnology - Abstract
Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM on hCmPCs. Results We found that following the double-strand break formation in hCmPCs caused by Dox, NPM was rapidly secreted in the extracellular space by an active mechanism, in the absence of either apoptosis or necrosis. Extracellular release of NPM was similarly seen in response to ultraviolet radiation (UV). Furthermore, we observed an increase of NPM levels in the plasma of Dox-treated mice; thus, NPM release also occurred in vivo. The treatment of hCmPCs with extracellular recombinant NPM induced a decrease of cell proliferation and a response mediated through the Toll-like receptor (TLR)4. We demonstrated that NPM binds to TLR4, and via TLR4, and nuclear factor kappa B (NFkB) activation/nuclear translocation, exerts proinflammatory functions by inducing IL-6 and COX-2 gene expression. Finally, we found that in hCmPCs, NPM secretion could be driven by an autophagy-dependent unconventional mechanism that requires TLR4, since TLR4 inhibition dramatically reduced Dox-induced secretion. Conclusions We hypothesise that the extracellular release of NPM could be a general response to DNA damage since it can be elicited by either a chemical agent such as Dox or a physical genotoxic stressor such as UV radiation. Following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and a TLR4/NFκB-dependent inflammatory response.
- Published
- 2021
13. Atherosclerotic plaque instability in carotid arteries: miR-200c as a promising biomarker
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Alessandro Platone, Marco D'Agostino, Alessandra Paolini, Sara Sileno, Sergio Furgiuele, Maurizio C. Capogrossi, Alessandra Magenta, Sara Beji, Francesca Persiani, and Daniele Camilli
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Genetic Markers ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Time Factors ,MMP1 ,medicine.medical_treatment ,Inflammation ,Carotid endarterectomy ,030204 cardiovascular system & hematology ,MMP9 ,Risk Assessment ,endothelial dysfunction ,atherosclerosis ,inflammation ,microRNA ,Medicine (all) ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Enos ,medicine ,Humans ,Carotid Stenosis ,Endothelial dysfunction ,Interleukin 6 ,Aged ,Ultrasonography ,Endarterectomy, Carotid ,Rupture, Spontaneous ,biology ,business.industry ,General Medicine ,medicine.disease ,biology.organism_classification ,Plaque, Atherosclerotic ,MicroRNAs ,Carotid Arteries ,Treatment Outcome ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,Biomarker (medicine) ,Female ,medicine.symptom ,business - Abstract
Early recognition of vulnerable carotid plaques could help in identifying patients at high stroke risk, who may benefit from earlier revascularisation. Nowadays, different biomarkers of plaque instability have been unravelled, among these miRNAs are promising tools for the diagnosis and treatment of atherosclerosis. Inflammation, reactive oxygen species (ROS) and endothelial dysfunction play a key role in unstable plaques genesis. We showed that miR-200c induces endothelial dysfunction, ROS production and a positive mechanism among miR-200c and miR-33a/b, two miRNAs involved in atherosclerosis progression. The goal of the present study was to determine whether miR-200c could be an atherosclerosis biomarker. Carotid plaques of patients that underwent carotid endarterectomy (CEA) were assayed for miR-200c expression. miR-200c was up-regulated in carotid plaques (n=22) and its expression was higher in unstable (n=12) compared with stable (n=10) plaques. miR-200c positively correlated with instability biomarkers (i.e. monocyte chemoattractant protein-1, cicloxigenase-2 (COX2), interleukin 6 (IL6), metalloproteinase (MMP) 1 (MMP1), 9 (MMP9)) and miR-33a/b. Moreover, miR-200c negatively correlated with stability biomarkers (i.e. zinc finger E-box binding homoeobox 1 (ZEB1), endothelial nitric oxide (NO) synthase (eNOS), forkhead boxO1 (FOXO1) and Sirtuin1 (SIRT1)) (stable plaques = 15, unstable plaques = 15). Circulating miR-200c was up-regulated before CEA in 24 patients, correlated with miR-33a/b and decreased 1 day after CEA. Interestingly, 1 month after CEA, circulating miR-200c is low in patients with stable plaques (n=11) and increased to control levels, in patients with unstable plaques (n=13). Further studies are needed to establish whether miR-200c represents a circulating biomarker of plaque instability. Our results show that miR-200c is an atherosclerotic plaque progression biomarker and suggest that it may be clinically useful to identify patients at high embolic risk.
- Published
- 2018
14. Share MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo
- Author
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Luisa de Latouliere 1, Isabella Manni 2, Laura Ferrari 3, Federica Pisati 4, Maria Grazia Totaro 3, Aymone Gurtner 5 6, Emanuele Marra 7 8, Lucrezia Pacello 7, Ombretta Pozzoli 9 10, Luigi Aurisicchio 7 8, Maurizio C Capogrossi 11 12, Gianluca Deflorian 3 13, and Giulia Piaggio 5
- Subjects
Confocal microscopy ,Cell growth ,animal structures ,fungi ,Regeneration ,Genetic models ,Bioluminescence imaging - Abstract
We developed a novel reporter transgenic zebrafish model called MITO-Luc/GFP zebrafish in which GFP and luciferase expression are under the control of the master regulator of proliferation NF-Y. In MITO-Luc/GFP zebrafish it is possible to visualize cell proliferation in vivo by fluorescence and bioluminescence. In this animal model, GFP and luciferase expression occur in early living embryos, becoming tissue specific in juvenile and adult zebrafish. By in vitro and ex vivo experiments we demonstrate that luciferase activity in adult animals occurs in intestine, kidney and gonads, where detectable proliferating cells are located. Further, by time lapse experiments in live embryos, we observed a wave of GFP positive cells following fin clip. In adult zebrafish, in addition to a bright bioluminescence signal on the regenerating tail, an early unexpected signal coming from the kidney occurs indicating not only a fin cell proliferation, but also a systemic response to tissue damage. Finally, we observed that luciferase activity was inhibited by anti-proliferative interventions, i.e. 5FU, cell cycle inhibitors and X-Rays. In conclusion, MITO-Luc/GFP zebrafish is a novel animal model that may be crucial to assess the spatial and temporal evolution of cell proliferation in vivo.
- Published
- 2021
15. Aging- and gender-related modulation of RAAS: potential implications in COVID-19 disease
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Laura Monteonofrio, Majd AlGhatrif, Maria Cristina Florio, Edward G. Lakatta, and Maurizio C. Capogrossi
- Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system ,lcsh:QP1-981 ,Coronavirus disease 2019 (COVID-19) ,business.industry ,aging ,COVID-19 ,ACE2 ,Disease ,Review ,medicine.disease ,lcsh:Physiology ,Pneumonia ,Respiratory failure ,lcsh:RC666-701 ,Infectious disease (medical specialty) ,cardiovascular disease ,Immunology ,Renin–angiotensin system ,Angiotensin-converting enzyme 2 ,gender ,Medicine ,business ,Receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Coronavirus disease 2019 (COVID-19) is a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is frequently characterized by a marked inflammatory response with severe pneumonia and respiratory failure associated with multiorgan involvement. Some risk factors predispose patients to develop a more severe infection and to an increased mortality; among them, advanced age and male gender have been identified as major and independent risk factors for COVID-19 poor outcome. The renin-angiotensin-aldosterone system (RAAS) is strictly involved in COVID-19 because angiotensin converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 and also converts pro-inflammatory angiotensin (Ang) II into anti-inflammatory Ang(1–7). In this review, we have addressed the effect of aging and gender on RAAS with emphasis on ACE2, pro-inflammatory Ang II/Ang II receptor 1 axis and anti-inflammatory Ang(1–7)/Mas receptor axis.
- Published
- 2020
16. MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo
- Author
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Lucrezia Pacello, Maria Grazia Totaro, Isabella Manni, Luigi Aurisicchio, Maurizio C. Capogrossi, Federica Pisati, Ombretta Pozzoli, Giulia Piaggio, Gianluca Deflorian, Aymone Gurtner, Luisa de Latouliere, Emanuele Marra, and Laura Ferrari
- Subjects
animal structures ,Science ,Green Fluorescent Proteins ,Biology ,Article ,Green fluorescent protein ,Animals, Genetically Modified ,Evolution, Molecular ,Cell growth ,Spatio-Temporal Analysis ,In vivo ,Bioluminescence ,Animals ,Regeneration ,Luciferase ,Luciferases ,Zebrafish ,Cell Proliferation ,Bioluminescence imaging ,Multidisciplinary ,fungi ,Cell cycle ,biology.organism_classification ,Genetic models ,Cell biology ,Confocal microscopy ,Medicine ,Ex vivo - Abstract
We developed a novel reporter transgenic zebrafish model called MITO-Luc/GFP zebrafish in which GFP and luciferase expression are under the control of the master regulator of proliferation NF-Y. In MITO-Luc/GFP zebrafish it is possible to visualize cell proliferation in vivo by fluorescence and bioluminescence. In this animal model, GFP and luciferase expression occur in early living embryos, becoming tissue specific in juvenile and adult zebrafish. By in vitro and ex vivo experiments we demonstrate that luciferase activity in adult animals occurs in intestine, kidney and gonads, where detectable proliferating cells are located. Further, by time lapse experiments in live embryos, we observed a wave of GFP positive cells following fin clip. In adult zebrafish, in addition to a bright bioluminescence signal on the regenerating tail, an early unexpected signal coming from the kidney occurs indicating not only a fin cell proliferation, but also a systemic response to tissue damage. Finally, we observed that luciferase activity was inhibited by anti-proliferative interventions, i.e. 5FU, cell cycle inhibitors and X-Rays. In conclusion, MITO-Luc/GFP zebrafish is a novel animal model that may be crucial to assess the spatial and temporal evolution of cell proliferation in vivo.
- Published
- 2020
17. Aging, MicroRNAs, and Heart Failure
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Edward G. Lakatta, Maurizio C. Capogrossi, Alessandra Magenta, Maria Cristina Florio, and Sara Beji
- Subjects
Regulation of gene expression ,Ejection fraction ,microRNA ,business.industry ,aging ,heart failure ,General Medicine ,030204 cardiovascular system & hematology ,Bioinformatics ,medicine.disease ,03 medical and health sciences ,MicroRNAs ,0302 clinical medicine ,Gene Expression Regulation ,Heart failure ,Gene expression ,Medicine ,Humans ,030212 general & internal medicine ,Risk factor ,Cardiology and Cardiovascular Medicine ,business ,Heart failure with preserved ejection fraction ,Aged - Abstract
Aging is a major risk factor for heart failure, one of the leading causes of death in Western society. The mechanisms that underlie the different forms of heart failure have been elucidated only in part and the role of noncoding RNAs is still poorly characterized. Specifically, microRNAs (miRNAs), a class of small noncoding RNAs that can modulate gene expression at the posttranscriptional level in all cells, including myocardial and vascular cells, have been shown to play a role in heart failure with reduced ejection fraction. In contrast, miRNAs role in heart failure with preserved ejection fraction, the predominant form of heart failure in the elderly, is still unknown. In this review, we will focus on age-dependent miRNAs in heart failure and on some other conditions that are prevalent in the elderly and are frequently associated with heart failure with preserved ejection fraction.
- Published
- 2020
18. Molecular therapies delaying cardiovascular aging: disease- or health-oriented approaches
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Maurizio C. Capogrossi, Sunayana Begum Syed, Paolo Madeddu, Reggio Lorde, Alessandra Magenta, and Annibale Alessandro Puca
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Senescence ,lcsh:Diseases of the circulatory (Cardiovascular) system ,media_common.quotation_subject ,epigenetics ,genetics ,vascular regeneration ,Bristol Heart Institute ,Druggability ,Review ,Disease ,Bioinformatics ,Regenerative medicine ,lcsh:Physiology ,Medicine ,Epigenetics ,media_common ,lcsh:QP1-981 ,business.industry ,Regeneration (biology) ,Longevity ,Review article ,lcsh:RC666-701 ,business - Abstract
Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.
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- 2020
19. The Janus face of HMGB1 in heart disease: a necessary update
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Francesco Scavello, Marco Bianchi, Maurizio C. Capogrossi, Alessandro d’Ambrosio, Angela Raucci, Stefania Di Maggio, Raucci, Angela, Di Maggio, Stefania, Scavello, Francesco, D’Ambrosio, Alessandro, Bianchi, Marco E., and Capogrossi, Maurizio C.
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0301 basic medicine ,Myocarditis ,Heart Diseases ,Nucleosome assembly ,Myocarditi ,Myocardial Infarction ,chemical and pharmacologic phenomena ,Inflammation ,Review ,030204 cardiovascular system & hematology ,HMGB1 ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Extracellular ,Alarmins ,Animals ,Humans ,Regeneration ,HMGB1 Protein ,Molecular Biology ,Pharmacology ,biology ,Animal ,business.industry ,Regeneration (biology) ,Oxidative Stre ,Biomarker ,Cell Biology ,medicine.disease ,Cell biology ,Oxidative Stress ,Heart Disease ,030104 developmental biology ,Alarmin ,biology.protein ,Molecular Medicine ,medicine.symptom ,Reactive Oxygen Species ,Reactive Oxygen Specie ,business ,Reperfusion injury ,Biomarkers ,Oxidative stress ,Human - Abstract
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein involved in transcription regulation, DNA replication and repair and nucleosome assembly. HMGB1 is passively released by necrotic tissues or actively secreted by stressed cells. Extracellular HMGB1 acts as a damage-associated molecular pattern (DAMPs) molecule and gives rise to several redox forms that by binding to different receptors and interactors promote a variety of cellular responses, including tissue inflammation or regeneration. Inhibition of extracellular HMGB1 in experimental models of myocardial ischemia/reperfusion injury, myocarditis, cardiomyopathies induced by mechanical stress, diabetes, bacterial infection or chemotherapeutic drugs reduces inflammation and is protective. In contrast, administration of HMGB1 after myocardial infarction induced by permanent coronary artery ligation ameliorates cardiac performance by promoting tissue regeneration. HMGB1 decreases contractility and induces hypertrophy and apoptosis in cardiomyocytes, stimulates cardiac fibroblast activities, and promotes cardiac stem cell proliferation and differentiation. Interestingly, maintenance of appropriate nuclear HMGB1 levels protects cardiomyocytes from apoptosis by preventing DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac damage. Finally, higher levels of circulating HMGB1 are associated to human heart diseases. Hence, during cardiac injury, HMGB1 elicits both harmful and beneficial responses that may in part depend on the generation and stability of the diverse redox forms, whose specific functions in this context remain mostly unexplored. This review summarizes recent findings on HMGB1 biology and heart dysfunctions and discusses the therapeutic potential of modulating its expression, localization, and oxidative-dependent activities.
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- 2018
20. miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase)
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Marco Bianchi, Francesca Brambilla, Angela Raucci, Ileana Badi, Claudio Saccu, Andrea Polizzotto, Giulio Pompilio, Debora Ferri, Giuseppina Milano, Maurizio C. Capogrossi, Ilaria Burba, Luigi Mancinelli, Filippo Zeni, Badi, Ileana, Mancinelli, Luigi, Polizzotto, Andrea, Ferri, Debora, Zeni, Filippo, Burba, Ilaria, Milano, Giuseppina, Brambilla, Francesca, Saccu, Claudio, Bianchi, Marco E, Pompilio, Giulio, Capogrossi, Maurizio C, and Raucci, Angela
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Male ,0301 basic medicine ,Aging ,Vascular smooth muscle ,Core Binding Factor Alpha 1 Subunit ,030204 cardiovascular system & hematology ,Muscle, Smooth, Vascular ,Mice ,0302 clinical medicine ,Sirtuin 1 ,animal ,Aorta ,Cells, Cultured ,Cellular Senescence ,Mice, Knockout ,biology ,Chemistry ,Transdifferentiation ,SOX9 Transcription Factor ,Up-Regulation ,Cell biology ,vascular calcification ,Cardiology and Cardiovascular Medicine ,Adult ,Senescence ,mice ,Myocytes, Smooth Muscle ,Down-Regulation ,Young Adult ,03 medical and health sciences ,Downregulation and upregulation ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,human ,Vascular Calcification ,Aging/pathology ,Aorta/metabolism ,Cell Proliferation ,Cellular Senescence/physiology ,Core Binding Factor Alpha 1 Subunit/metabolism ,MicroRNAs/metabolism ,Muscle, Smooth, Vascular/cytology ,Muscle, Smooth, Vascular/metabolism ,Myocytes, Smooth Muscle/metabolism ,Proto-Oncogene Proteins/metabolism ,Receptor Protein-Tyrosine Kinases/metabolism ,SOX9 Transcription Factor/metabolism ,Sirtuin 1/metabolism ,aging ,humans ,senescence ,AXL receptor tyrosine kinase ,Cell growth ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Axl Receptor Tyrosine Kinase ,MicroRNAs ,030104 developmental biology ,biology.protein ,Calcification - Abstract
Objective— Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results— We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a +/+ and Mir34a −/− mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a −/− SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a +/+ cells. Furthermore, unlike in Mir34a +/+ SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a −/− SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions— miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.
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- 2018
21. Nuclear Hmgb1
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Angela Raucci and Maurizio C. Capogrossi
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HMGB1 ,medicine.medical_specialty ,biology ,DNA damage ,business.industry ,cardiac hypertrophy ,heart failure ,Failing heart ,medicine.disease ,Heart failure ,Internal medicine ,Cardiac hypertrophy ,biology.protein ,Cardiology ,medicine ,Cardiology and Cardiovascular Medicine ,business ,Editorial Comment - Abstract
Corresponding Author
- Published
- 2019
22. Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction
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Alessandro d’Ambrosio, Matteo Bertolotti, Giulio Pompilio, Giuseppina Milano, Ileana Badi, Stefania Di Maggio, Elena Sommariva, Maurizio C. Capogrossi, Francesco De Marchis, Angela Raucci, and Blanca Soler Palacios
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Male ,0301 basic medicine ,Receptors, CXCR4 ,Myocardial Infarction ,Infarction ,chemical and pharmacologic phenomena ,HMGB1 ,03 medical and health sciences ,Cell Movement ,Fibrosis ,medicine ,Humans ,HMGB1 Protein ,Receptor ,Molecular Biology ,biology ,Chemistry ,Myocardium ,Chemotaxis ,Fibroblasts ,medicine.disease ,Chemokine CXCL12 ,Cell biology ,030104 developmental biology ,Immunology ,biology.protein ,TLR4 ,Molecular Medicine ,Female ,Oxidation-Reduction ,Myofibroblast ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Myocardial infarction (MI) is a major health burden worldwide. Extracellular High mobility group box 1 (HMGB1) regulates tissue healing after injuries. The reduced form of HMGB1 (fr-HMGB1) exerts chemotactic activity by binding CXCL12 through CXCR4, while the disulfide form, (ds-HMGB1), induces cytokines expression by TLR4. Here, we assessed the role of HMGB1 redox forms and the non-oxidizable mutant (3S) on human cardiac fibroblast (hcFbs) functions and cardiac remodeling after infarction. Among HMGB1 receptors, hcFbs express CXCR4. Fr-HMGB1 and 3S, but not ds-HMGB1, promote hcFbs migration through Src activation, while none of HMGB1 redox forms induces proliferation or inflammatory mediators. 3S is more effective than fr-HMGB1 in stimulating hcFbs migration and Src phosphorylation being active at lower concentrations and in oxidizing conditions. Notably, chemotaxis toward both proteins is CXCR4-dependent but, in contrast to fr-HMGB1, 3S does not require CXCL12 since hcFbs migration persists in the presence of the CXCL12/CXCR4 inhibitor AMD3100 or an anti-CXCL12 antibody. Interestingly, 3S interacts with CXCR4 and induces a different receptor conformation than CXCL12. Mice undergoing MI and receiving 3S exhibit adverse LV remodeling owing to an excessive collagen deposition promoted by a higher number of myofibroblasts. On the contrary, fr-HMGB1 ameliorates cardiac performance enhancing neoangiogenesis and reducing the infarcted area and fibrosis. Altogether, our results demonstrate that non-oxidizable HMGB1 induce a sustained cardiac fibroblasts migration despite the redox state of the environment and by altering CXCL12/CXCR4 axis. This affects proper cardiac remodeling after an infarction.
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- 2017
23. Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop Among SIRT1, FOXO1, and eNOS
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Alessio Torcinaro, Fabio Martelli, Daniele Avitabile, Roberto Rizzi, Biagina Maimone, Alessandra Magenta, Valeria Di Stefano, Sara Beji, Marco D'Agostino, Maurizio C. Capogrossi, Roberta Ciarapica, Annalisa Antonini, Fabrizio Carlomosti, Elena Dellambra, Francesca De Santa, Germana Zaccagnini, and Sonia Cordisco
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Male ,0301 basic medicine ,Physiology ,Clinical Biochemistry ,FOXO1 ,medicine.disease_cause ,Biochemistry ,Mice ,chemistry.chemical_compound ,Sirtuin 1 ,Enos ,Protein phosphorylation ,Phosphorylation ,Cells, Cultured ,General Environmental Science ,chemistry.chemical_classification ,aging ,free radicals ,microRNA ,nitric oxide ,vascular ,biology ,Forkhead Box Protein O1 ,food and beverages ,Acetylation ,Cell biology ,hormones, hormone substitutes, and hormone antagonists ,Senescence ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Nitric Oxide Synthase Type III ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Molecular Biology ,Reactive oxygen species ,Cell Biology ,Fibroblasts ,biology.organism_classification ,Disease Models, Animal ,MicroRNAs ,Oxidative Stress ,HEK293 Cells ,030104 developmental biology ,chemistry ,biology.protein ,General Earth and Planetary Sciences ,Reactive Oxygen Species ,Oxidative stress - Abstract
Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging. We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated.We demonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR-200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia. Antioxid. Redox Signal. 27, 328-344.
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- 2017
24. The double life of cardiac mesenchymal cells: Epimetabolic sensors and therapeutic assets for heart regeneration
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Antonella Farsetti, Francesco Spallotta, Maurizio C. Capogrossi, Carlo Gaetano, Andreas M. Zeiher, Chiara Cencioni, Matteo Savoia, Sandra Atlante, and Fabio Martelli
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0301 basic medicine ,regenerative medicine ,Clinical uses of mesenchymal stem cells ,Biology ,Cardiac fibroblast ,Exosome ,Regenerative medicine ,Epigenesis, Genetic ,03 medical and health sciences ,Risk Factors ,medicine ,Animals ,Humans ,Regeneration ,Pharmacology (medical) ,Epigenetics ,Cardiovascular diseases ,Mesenchymal stem cells ,Metabolism ,Cardiac muscle cell ,Pharmacology ,mesenchymal stem cells ,epigenetics ,Myocardium ,Regeneration (biology) ,Mesenchymal stem cell ,Heart ,Fibroblasts ,cardiovascular diseases ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Pericyte ,Pericytes ,metabolism ,Neuroscience - Abstract
Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms. Intriguingly, the heart is emerging as a source of different cells, including pericytes, cardiac progenitors, and cardiac fibroblasts. According to phenotypic, functional, and molecular criteria, these should be classified as mesenchymal cells. Not surprisingly, in recent years, the attention on these cells as therapeutic tools has grown exponentially, although only very preliminary data have been obtained in clinical trials to date. In this review, we summarized the state of the art about the phenotypic features, functions, regenerative properties, and clinical applicability of mesenchymal cells, with a particular focus on those of cardiac origin.
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- 2017
25. High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction
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Luis Cuniberti, Carlos Sebastián Giménez, Maurizio C. Capogrossi, Andrea De Lorenzi, Anna Hnatiuk, Fernanda Daniela Olea, Maria del Rosario Bauza, Alberto J. Crottogini, and Paola Locatelli
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Male ,medicine.medical_specialty ,Cardiotonic Agents ,CIENCIAS MÉDICAS Y DE LA SALUD ,TBX20 ,Angiogenesis ,Myocardial Infarction ,Pharmaceutical Science ,02 engineering and technology ,Placebo ,HMGB1 ,030226 pharmacology & pharmacy ,Ventricular Function, Left ,ACUTE MYOCARDIAL INFARCTION ,Biotecnología de la Salud ,03 medical and health sciences ,CARDIOPROTECTION ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Myocardial infarction ,purl.org/becyt/ford/3.4 [https] ,HMGB1 Protein ,Cardioprotection ,Ejection fraction ,Sheep ,Tecnologías que involucran la manipulación de células, tejidos, órganos o todo el organismo ,biology ,business.industry ,Myocardium ,Microvascular Density ,021001 nanoscience & nanotechnology ,medicine.disease ,SHEEP ,Microvessels ,Cardiology ,biology.protein ,purl.org/becyt/ford/3 [https] ,Female ,0210 nano-technology ,business - Abstract
In rodents with acute myocardial infarction (AMI), high mobility group box 1 (HMGB1) injection has produced controversial results. Given the lack of data in large mammals, we searched the dose that would promote angiogenesis and expression of specific regenerative genes in sheep with AMI (protocol 1) and, subsequently, use this dose to study long-term effects on infarct size and left ventricular (LV) function (protocol 2). Protocol 1: Sheep with AMI received 250 μg (high-dose, n = 7), 25 μg (low-dose, n = 7) HMGB1, or PBS (placebo, n = 7) in 10 intramyocardial injections (0.2 ml each) in the peri-infarct area. Seven days later, only the high-HMGB1-dose group exhibited higher microvascular densities, Ki67-positive cardiomyocytes, and overexpression of VEGF, Ckit, Tbx20, Nkx2.5, and Gata4. Protocol 2: Sheep with AMI received HMGB1 250 μg (n = 6) or PBS (n = 6). At 60 days, HMGB1-treated sheep showed smaller infarcts (8.5 ± 2.11 vs. 12.2 ± 1.97% LV area, P < 0.05, ANOVA-Bonferroni) and higher microvascular density (capillaries, 1798 ± 252 vs. 1266 ± 250/mm2; arterioles, 18.3 ± 3.9 vs. 11.7 ± 2.2/mm2; both P < 0.01). Echocardiographic LV ejection fraction, circumferential shortening, and wall thickening increased from day 3 to 60 with HMGB1 (all P < 0.05). Conclusion: in ovine AMI, high-dose HMGB1 induces angio-arteriogenesis, reduces infarct size, and improves LV function at 2 months post-treatment. Fil: Bauza, Maria del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Giménez, Carlos Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Locatelli, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: De Lorenzi, Andrea. Fundación Favaloro; Argentina Fil: Hnatiuk, Anna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Capogrossi, Maurizio C.. Johns Hopkins Bayview Medical Center; Estados Unidos Fil: Crottogini, Alberto José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Cuniberti, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Olea, Fernanda Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina
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- 2019
26. The Oxidative Stress-Induced miR-200c Is Upregulated in Psoriasis and Correlates with Disease Severity and Determinants of Cardiovascular Risk
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L. Di Vito, Francesco Barillà, Maurizio C. Capogrossi, Guido Melillo, Cristina Albanesi, Monica Napolitano, D Abeni, Stefania Madonna, C Uras, Sara Sileno, Marco D'Agostino, Francesco Martino, and Alessandra Magenta
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Male ,Risk ,0301 basic medicine ,Senescence ,Aging ,medicine.medical_specialty ,Article Subject ,Endothelium ,Inflammation ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Severity of Illness Index ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Psoriasis Area and Severity Index ,Psoriasis ,Internal medicine ,medicine ,Humans ,oxidative stress ,lcsh:QH573-671 ,Endothelial dysfunction ,Skin ,microRNA ,lcsh:Cytology ,business.industry ,Cell Biology ,General Medicine ,psoriasis ,Middle Aged ,medicine.disease ,Up-Regulation ,cardiovascular diseases ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Blood pressure ,Endocrinology ,Disease Progression ,Female ,Endothelium, Vascular ,medicine.symptom ,Reactive Oxygen Species ,business ,Biomarkers ,Oxidative stress ,Research Article - Abstract
Psoriasis is a chronic inflammatory skin disease associated with reactive oxygen species (ROS) increase and a higher risk of cardiovascular (CV) events. We previously showed that the miR-200 family (miR-200s) is induced by ROS, miR-200c being the most upregulated member responsible for apoptosis, senescence, ROS increase, and nitric oxide decrease, finally causing endothelial dysfunction. Moreover, circulating miR-200c increases in familial hypercholesterolemic children and in plaques and plasma of atherosclerotic patients, two pathologies associated with increased ROS. Given miR-200s’ role in endothelial dysfunction, ROS, and inflammation, we hypothesized that miR-200s were modulated in lesional skin (LS) and plasma of psoriatic patients (Pso) and that their levels correlated with some CV risk determinants at a subclinical level. All Pso had severe psoriasis, i.e., Psoriasis Area and Severity Index PASI>10, and one of the following: at least two systemic psoriasis treatments, age at onset<40 years, and disease duration>10 years. RNA was extracted from plasma (Pso, N=29; Ctrl, N=29) and from nonlesional skin (NLS) and LS of 6 Pso and 6 healthy subject skin (HS) biopsies. miR-200 levels were assayed by quantitative RT-PCR. We found that all miR-200s were increased in LS vs. NLS and miR-200c was the most expressed and upregulated in LS vs. HS. In addition, circulating miR-200c and miR-200a were upregulated in Pso vs. Ctrl. Further, miR-200c positively correlated with PASI, disease duration, left ventricular (LV) mass, LV relative wall thickness (RWT), and E/e′, a marker of diastolic dysfunction. Multiple regression analysis indicates a direct association between miR-200c and both RWT and LV mass. Circulating miR-200a correlated positively only with LV mass and arterial pressure augmentation index, a measure of stiffness, although the correlations were nearly significant (P=0.06). In conclusion, miR-200c is upregulated in LS and plasma of Pso, suggesting its role in ROS increase and inflammation associated with CV risk in psoriasis.
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- 2019
27. Power Is Nothing Without Control
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Beatrice Bassetti, Giulio Pompilio, and Maurizio C. Capogrossi
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Heart Diseases ,Heart disease ,Physiology ,Cell ,Cell- and Tissue-Based Therapy ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,medicine ,Animals ,Humans ,Regeneration ,Myocytes, Cardiac ,030212 general & internal medicine ,business.industry ,medicine.disease ,Clinical trial ,medicine.anatomical_structure ,Clinical research ,Heart failure ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,Stem Cell Transplantation ,Adult stem cell - Abstract
> A few observation and much reasoning lead to error; many observations and a little reasoning to truth. > > —Alexis Carrel, Medicine Nobel Prize 1912 Cardiac cell–based therapy, after a peak of untimely expectations of miraculous efficacy exceeding standard clinical practice, has faced the cardiological community and funding bodies with a predictable trough of disillusionment. In the light of more recent progresses, the field is by contrast moving toward a competitive differentiation phase, in which the resolution of the complex matching between potency of cell therapeutics and heart disease pathophysiology has the potential to make a difference for the most challenging unmet clinical needs in cardiovascular medicine. The exogenous administration of stem cells to repair the damaged heart has been clinically introduced on the basis of the revolutionary idea that by delivering cardiomyogenic potent cells, the substitution of dead or damaged myocardium with de novo cardiomyocytes able to directly contribute to contractile force generation would have been an achievable target. The confirmation that the heart possesses an intrinsic, although modest, self-renewal capacity1 has further fueled the clinical exploitation of such an innovative therapeutic strategy. However, from the progress in the field over the past 15 years, it has become evident that by means of available clinical-grade cell products, the salutary functional and clinical effects of cardiac cell therapy (CCT), when present, are more likely because of an indirect (paracrine) action exerted by cells nested in the myocardium through the release of a miscellany of largely unidentified molecules, which promote endogenous reparative processes. Such a paradigm shift from a cardiopoietic to a cardioreparative concept may have profound implications for forthcoming CCT clinical research. Notably, different classes of compounds with a cardioprotective action have been recently unsuccessfully tested in clinical trials with the aim to prevent ischemia–reperfusion injury or heart failure (HF) progression. …
- Published
- 2016
28. Cyclophilin A modulates bone marrow-derived CD117+ cells and enhances ischemia-induced angiogenesis via the SDF-1/CXCR4 axis
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Maria Corlianò, Gianluca Lorenzo Perrucci, Maurizio C. Capogrossi, Patrizia Nigro, Alessandro Scopece, Giulio Pompilio, Stefania Straino, Bradford C. Berk, Federico Lombardi, and Monica Napolitano
- Subjects
0301 basic medicine ,Programmed cell death ,Pathology ,medicine.medical_specialty ,Receptors, CXCR4 ,Angiogenesis ,Cell ,Ischemia ,Neovascularization, Physiologic ,Cypa ,Bone Marrow Cells ,030204 cardiovascular system & hematology ,CD117+ cells ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,medicine ,Cell Adhesion ,Animals ,Humans ,Cell adhesion ,Cells, Cultured ,Cell Proliferation ,biology ,Cell growth ,business.industry ,medicine.disease ,biology.organism_classification ,Hind-limb ischemia ,digestive system diseases ,Chemokine CXCL12 ,3. Good health ,Hindlimb ,Mice, Inbred C57BL ,Disease Models, Animal ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Bone marrow ,business ,Cardiology and Cardiovascular Medicine ,SDF-1/CXCR4 axis ,Cyclophilin A ,Neo-angiogenesis ,Signal Transduction - Abstract
Background Critical limb ischemia (CLI) is a major health problem with no adequate treatment. Since CLI is characterized by insufficient tissue vascularization, efforts have focused on the discovery of novel angiogenic factors. Cyclophilin A (CyPA) is an immunophilin that has been shown to promote angiogenesis in vitro and to enhance bone marrow (BM) cell mobilization in vivo . However, its potential as an angiogenic factor in CLI is still unknown. Thus, this study aimed to evaluate whether CyPA might induce neo-angiogenesis in ischemic tissues. Methods and results Wild-type C57Bl/6j mice underwent acute hind-limb ischemia (HLI) and received a single intramuscular administration of recombinant CyPA or saline. Limb perfusion, capillary density and arteriole number in adductor muscles were significantly increased after CyPA treatment. Interestingly, BM-derived CD117 + cell recruitment was significantly higher in ischemic adductor tissue of mice treated with CyPA versus saline. Therefore, the effect of CyPA on isolated BM-derived CD117 + cells in vitro was evaluated. Low concentrations of CyPA stimulated CD117 + cell proliferation while high concentrations promoted cell death. Moreover, CyPA enhanced CD117 + cell adhesion and migration in a dose-dependent manner. Mechanistic studies revealed that CyPA up-regulated CXCR4 in CD117 + cells and in adductor muscles after ischemia. Additionally, SDF-1/CXCR4 axis inhibition by the CXCR4 antagonist AMD3100 decreased CyPA-mediated CD117 + cell recruitment in the ischemic limb. Conclusion CyPA induces neo-angiogenesis by recruiting BM-derived CD117 + cell into ischemic tissues, at least in part, through SDF-1/CXCR4 axis.
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- 2016
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29. Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy
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Gualtiero I. Colombo, Viviana Meraviglia, Corrado Carbucicchio, Michela Casella, Gianluca Pontone, Floriana Maria Farina, Mattia Chiesa, A. Dello Russo, Carmela Preziuso, Maurizio C. Capogrossi, Elena Sommariva, Claudio Tondo, N. Ouali Alami, Ilaria Stadiotti, Adolfo Paolin, Elisa Gambini, Silvia Brambilla, Giulia d'Amati, Giulio Pompilio, Elisa Cogliati, Valentina Catto, and Alessandra Rossini
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Adult ,Male ,0301 basic medicine ,Cell type ,medicine.medical_specialty ,Cardiomyopathy ,Plakoglobin ,030204 cardiovascular system & hematology ,Sudden death ,plakophilin2 ,03 medical and health sciences ,0302 clinical medicine ,Basic Science ,Internal medicine ,Lipid droplet ,Adipocytes ,medicine ,Humans ,Arrhythmogenic Right Ventricular Dysplasia ,Cells, Cultured ,Adipogenesis ,fibrofatty substitution ,business.industry ,adipogenesis ,arrhythmogenic cardiomyopathy ,mesenchymal stromal cells ,plakoglobin ,adipocytes ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Middle Aged ,Cell cycle ,Lipid Metabolism ,medicine.disease ,030104 developmental biology ,Endocrinology ,Cancer research ,Female ,gamma Catenin ,Cardiology and Cardiovascular Medicine ,business ,Plakophilins - Abstract
Aim Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C-MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. Methods and results We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C-MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. controls. Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C-MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. Conclusions Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patient-specific in vitro tool for future mechanistic studies.
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- 2015
30. Role of psoriasis on subclinical cardiovascular disease
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G Melillo, Claudia Uras, Maurizio C. Capogrossi, Roberta Ciarapica, Luca Divito, Damiano Abeni, and Alessandra Magenta
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,business.industry ,General Medicine ,Disease ,Middle Aged ,medicine.disease ,Risk Assessment ,Dermatology ,03 medical and health sciences ,Vascular Stiffness ,030104 developmental biology ,Cardiovascular Diseases ,Psoriasis ,medicine ,Humans ,Female ,Hypertrophy, Left Ventricular ,Prospective Studies ,business ,Subclinical infection - Abstract
Systemic inflammation may induce atherosclerosis progression and psoriasis may represent an independent risk factor for atherosclerosis1. We assessed indexes of left ventricular (LV) hypertrophy and arterial stiffness in patients at low or high cardiovascular risk . We show that psoriatic patients at both low and high cardiovascular risk have an increased prevalence of LV concentric remodeling, but no differences were found in terms of E/e', probably because LV diastolic dysfunction represents an advanced marker of ventricular impairment.In conclusion, LV concentric remodeling, but not increased arterial stiffness, was more common in psoriatic patients at low CV. LV concentric remodeling and increased arterial stiffness were more prevalent in psoriatic patients at high CV risk. These data show that psoriasis may exert an additional negative effect on the cardiovascular system in patients with a higher prevalence of traditional CV risk factors.
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- 2018
31. Role of miR-200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice
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Giulia Imeneo, Maurizio C. Capogrossi, Marco D'Agostino, Sara Beji, Chiara Salis, Sara Sileno, Francesca De Santa, Lorenza Marchetti, Alessio Torcinaro, Luca Madaro, Daisy Proietti, and Alessandra Magenta
- Subjects
0301 basic medicine ,Senescence ,muscular dystrophy ,Aging ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Article Subject ,Duchenne muscular dystrophy ,Muscle Fibers, Skeletal ,myogenic differentiation ,MyoD ,medicine.disease_cause ,Muscle Development ,Biochemistry ,miR-200c ,Cell Line ,03 medical and health sciences ,Phosphoserine ,medicine ,Myocyte ,Animals ,Regeneration ,Muscular dystrophy ,lcsh:QH573-671 ,Phosphorylation ,Muscle, Skeletal ,microRNA, miR-200c, p66Shc, myogenic differentiation, muscular dystrophy ,microRNA ,Chemistry ,Myogenesis ,lcsh:Cytology ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,General Medicine ,Muscular Dystrophy, Animal ,medicine.disease ,Cell biology ,p66Shc ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Mice, Inbred mdx ,Oxidative stress ,Research Article - Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc−/− muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc−/− fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.
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- 2018
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32. Bone Marrow Cell Therapy for Ischemic Heart Disease
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Maurizio C. Capogrossi, Giulio Pompilio, Beatrice Bassetti, and Patrizia Nigro
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Cardioprotection ,Cardiac function curve ,medicine.medical_specialty ,Pathology ,Ejection fraction ,Physiology ,Angiogenesis ,business.industry ,medicine.disease ,Neovascularization ,Transplantation ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cardiology ,Myocardial infarction ,Bone marrow ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
In the past 15 years, bone marrow (BM) cell (BMC) therapy has emerged as a potential novel strategy for the treatment of ischemic heart disease (IHD). The fervor for this novel promising therapy arose from the first studies on BMC differentiation into cardiomyocyte-like cells.1 After this discovery, research proceeded rapidly from preclinical models to clinical studies to test BMC’s potential to recover cardiac function and facilitate scar healing in ischemic cardiomyopathy.2–6 To mention just a few pioneering in vivo studies, Tomita et al7 reported that in adult rats, BMC injection into a left ventricular (LV) cryoinjury-induced myocardial infarction (MI) promotes the generation of cardiomyocyte-like cells and neoangiogenesis. Concomitantly, Kocker et al8 showed that BMC therapy prevents cardiomyocyte apoptosis and stimulates neovascularization of the ischemic heart, leading to an improvement of LV ejection fraction (LVEF) and survival. Article, see p 558 Notably, after >15 years, the mechanisms through which BMCs exert cardioprotection in acute IHD and chronic IHD (CIHD) have not been completely unraveled yet. Different therapeutic properties have been ascribed to BMCs, including the ability to form new contractile cardiac tissue by differentiating into cardiomyocytes,9,10 as well as the capacity to limit ischemic damage through direct cell-mediated and indirect paracrine-mediated mechanisms, promoting the induction of angiogenesis, inhibition of cell death, and formation of scar tissue.11,12 Over the years, this latter concept has gained a broader consensus. Notwithstanding the uncertainties about mode of action, the large body of positive preclinical studies spurred enthusiasm for immediate clinical translation, taking advantage of the relatively easy accessibility of BM as a cell source. Hamano et al13 were the first, in 2001, to report a pilot clinical trial on the beneficial effects of BMC transplantation in patients with IHD. This landmark study …
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- 2015
33. The mitochondrial lncRNA ASncmtRNA-2 is induced in aging and replicative senescence in Endothelial Cells
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Andrea Lauri, Marco Zanobini, Giulio Pompilio, Maurizio C. Capogrossi, Ileana Badi, Angela Raucci, Yuri D'Alessandra, Patrizia Nigro, Matteo Bertolotti, and Valentina Bianchessi
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Male ,Senescence ,Aging ,Vascular smooth muscle ,RNA, Mitochondrial ,Ultraviolet Rays ,Molecular Sequence Data ,Myocytes, Smooth Muscle ,Cell ,Endogeny ,Biology ,Mitochondrion ,Mice ,microRNA ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Molecular Biology ,Aorta ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,Genetics ,Base Sequence ,Hydrogen Peroxide ,Cell cycle ,Mitochondria ,Cell biology ,Telomere ,G2 Phase Cell Cycle Checkpoints ,Mice, Inbred C57BL ,MicroRNAs ,medicine.anatomical_structure ,Gene Expression Regulation ,RNA ,RNA, Long Noncoding ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
Age-associated cardiovascular diseases are at least partially ascribable to vascular cell senescence. Replicative senescence (RS) and stress-induced premature senescence (SIPS) are provoked respectively by endogenous (telomere erosion) and exogenous (H2O2, UV) stimuli resulting in cell cycle arrest in G1 and G2 phases. In both scenarios, mitochondria-derived ROS are important players in senescence initiation. We aimed to define whether a mtDNA-transcribed long-non-coding-RNA (lncRNA), ASncmtRNA-2, has a role in vascular aging and senescence. Aortas of old mice, characterized by increased senescence, showed an increment in ASncmtRNA-2 expression. In vitro analysis of Endothelial Cells (EC) and Vascular Smooth Muscle Cells (VSMC) established that ASncmtRNA-2 is induced in EC, but not in VSMC, during RS. Surprisingly, ASncmtRNA-2 is not upregulated in two different EC SIPS scenarios, treated with H2O2 and UV. The p16 gene displayed similar ASncmtRNA-2 expression patterns, suggesting a possible co-regulation of the two genes. Interestingly, the expression of two miRNAs, hsa-miR-4485 and hsa-miR-1973, with perfect homology to the double strand region of ASncmtRNA-2 and originating at least in part from a mitochondrial transcript, was induced in RS, opening to the possibility that this lncRNA functions as a non-canonical precursor of these miRNAs. Cell cycle analysis of EC transiently over-expressing ASncmtRNA-2 revealed an accumulation of EC in the G2/M phase, but not in the G1 phase. We propose that ASncmtRNA-2 in EC might be involved in the RS establishment by participating in the cell cycle arrest in G2/M phase, possibly through the production of hsa-miR-4485 and hsa-miR-1973. This article is part of a Special Issue entitled: Mitochondria.
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- 2015
34. Peptidyl-prolyl isomerases: a full cast of critical actors in cardiovascular diseases
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Maurizio C. Capogrossi, Marco Zanobini, Patrizia Nigro, Giulio Pompilio, Aoife Gowran, and Gianluca Lorenzo Perrucci
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Physiology ,Biology ,Bioinformatics ,Cardiovascular System ,Tacrolimus Binding Proteins ,Cyclophilins ,Immunophilins ,Physiology (medical) ,Gene expression ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Endothelial dysfunction ,Peptidylprolyl isomerase ,Cardiovascular Agents ,Peptidylprolyl Isomerase ,medicine.disease ,NIMA-Interacting Peptidylprolyl Isomerase ,Biochemistry ,Cardiovascular Diseases ,Cardiovascular agent ,Protein folding ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Vascular Stenosis ,Signal Transduction - Abstract
Peptidyl-prolyl cis-trans-isomerases are a highly conserved family of immunophilins. The three peptidyl-prolyl cis-trans-isomerase subfamilies are cyclophilins, FK-506-binding proteins, and parvulins. Peptidyl-prolyl cis-trans-isomerases are expressed in multiple human tissues and regulate different cellular functions, e.g. calcium handling, protein folding, and gene expression. Moreover, these subfamilies have been shown to be consistently involved in several cardiac and vascular diseases including heart failure, arrhythmias, vascular stenosis, endothelial dysfunction, atherosclerosis, and hypertension. This review provides a concise description of the peptidyl-prolyl cis-trans-isomerases and presents an incisive selection of studies focused on their relationship with cardiovascular diseases.
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- 2015
35. c-kit+ cells: the tell-tale heart of cardiac regeneration?
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Patrizia Nigro, Marco Zanobini, Gianluca Lorenzo Perrucci, Maurizio C. Capogrossi, Aoife Gowran, and Giulio Pompilio
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Cardiac function curve ,Cell- and Tissue-Based Therapy ,Disease ,Bioinformatics ,Cell therapy ,Cardiac regeneration ,Cellular and Molecular Neuroscience ,Animals ,Humans ,Regeneration ,Medicine ,Myocytes, Cardiac ,Progenitor cell ,Molecular Biology ,Pharmacology ,business.industry ,Stem Cells ,Regeneration (biology) ,Heart ,Cell Biology ,Bench to bedside ,Proto-Oncogene Proteins c-kit ,Cardiovascular Diseases ,Immunology ,Cardiac repair ,Molecular Medicine ,business - Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. Although ongoing therapeutic strategies ameliorate symptoms and prolong life for patients with cardiovascular diseases, they do not solve the critical issue related to the loss of cardiac tissue. Accordingly, stem/progenitor cell therapy has emerged as a paramount approach for cardiac repair and regeneration. In this regard, c-kit(+) cells have animated much interest and controversy. These cells are self-renewing, clonogenic, and multipotent and display a noteworthy potential to differentiate into all cardiovascular lineages. However, their functional contribution to cardiomyocyte turnover is one of the centrally debated issues concerning their regenerative potential. Regardless, plentiful preclinical and clinical studies have been conducted which provide evidence for the capacity of c-kit(+) cells to improve cardiac function. The purpose of this review is to give a comprehensive, impartial, critical description and evaluation of the literature on c-kit(+) cells from bench to bedside in order to address their true potential, benefits and controversies.
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- 2015
36. The mitochondrial genome in aging and senescence
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Giulio Pompilio, Andrea Lauri, and Maurizio C. Capogrossi
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Senescence ,Aging ,Mitochondrial DNA ,Cell ,Mitochondrion ,Biology ,DNA, Mitochondrial ,Biochemistry ,microRNA ,Autophagy ,medicine ,Animals ,Humans ,Telomerase reverse transcriptase ,Telomerase ,Molecular Biology ,Cellular Senescence ,Organism ,Genetics ,chemistry.chemical_classification ,Reactive oxygen species ,Genome, Human ,Mitochondria ,Cell biology ,medicine.anatomical_structure ,Neurology ,chemistry ,Mutation ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species ,Signal Transduction ,Biotechnology - Abstract
Aging is characterized by a progressive decline in organism functions due to the impairment of all organs. The deterioration of both proliferative tissues in liver, skin and the vascular system, as well as of largely post-mitotic organs, such as the heart and brain could be attributed at least in part to cell senescence. In this review we examine the role of mitochondrial dysfunction and mtDNA mutations in cell aging and senescence. Specifically, we address how p53 and telomerase reverse transcriptase (TERT) activity switch their roles from cytoprotective to detrimental and also examine the role of microRNAs in cell aging. The proposed role of Reactive Oxygen Species (ROS), both as mutating agents and as signalling molecules, underlying these processes is also described.
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- 2014
37. P4480High mobility group box-1 (HMGB1) protein-induced cardioprotection in sheep with acute myocardial infarction
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Luis Cuniberti, Maurizio C. Capogrossi, Paola Locatelli, Fernanda Daniela Olea, Alberto J. Crottogini, Maria del Rosario Bauza, A. B. De Lorenzi, and Carlos Sebastián Giménez
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Cardioprotection ,medicine.medical_specialty ,biology ,business.industry ,Internal medicine ,medicine ,biology.protein ,Cardiology ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,HMGB1 ,medicine.disease ,business - Published
- 2017
38. Naturally Adipose Stromal Cell-Enriched Fat Graft: Comparative Polychromatic Flow Cytometry Study of Fat Harvested by Barbed or Blunt Multihole Cannula
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Alessio Caggiati, Antonia Germani, Anna Di Carlo, Giovanna Borsellino, Mario Picozza, and Maurizio C. Capogrossi
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Adult ,Pathology ,medicine.medical_specialty ,Stromal cell ,medicine.medical_treatment ,Adipose tissue ,Transplants ,Centrifugation ,Cell Separation ,030230 surgery ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Lipectomy ,medicine ,Cannula ,Humans ,medicine.diagnostic_test ,business.industry ,General Medicine ,Stromal vascular fraction ,Middle Aged ,Flow Cytometry ,Transplantation ,Adipose Tissue ,030220 oncology & carcinogenesis ,Liposuction ,Tissue and Organ Harvesting ,Surgery ,Female ,Stromal Cells ,business - Abstract
Background Fat grafts enriched with cells of the stromal vascular fraction (SVF), especially adipose-derived stromal cells (ASCs), exhibit significantly improved retention over non enriched, plain fat. Different types of liposuction cannulae may yield lipoaspirates with different subpopulations of cells. Moreover, preparation of adipose tissue for transplantation typically involves centrifugation, which creates a density gradient of fat. Objectives The authors sought to determine whether liposuction with a barbed or smooth cannula altered the enrichment of the SVF, and specifically ASCs, in low-density (LD) and high-density (HD) fractions of centrifuged adipose tissue. Methods Fat was harvested from 2 abdominal sites of 5 healthy women with a barbed or smooth multihole blunt-end cannula. After centrifugation, LD and HD fat fractions were digested with collagenase and analyzed by polychromatic flow cytometry to identify and enumerate distinct populations of cells. Results Overall cell yield and the number of immune cells were consistently higher in HD fractions than in LD fractions, regardless of the cannula employed. More living cells, and specifically more ASCs, populated the HD fractions of lipoaspirates obtained with a barbed cannula than with a smooth cannula. Conclusions In this study, lipoaspiration with a barbed cannula and isolation of the HD layer of centrifuged adipose tissue yielded maximal amounts of SVF cells, including ASCs.
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- 2017
39. The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation
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Giulia Regazzo, Paolo Ciana, Aymone Gurtner, Maurizio C. Capogrossi, Lucia Cicchillitti, Carmine Mancone, Manuela Spagnuolo, Marco Tripodi, Fabrizio Carlomosti, Giulia Dell'Omo, Maria Lucia Dell'Anna, Tonino Alonzi, Giulia Piaggio, Isabella Manni, Mauro Picardo, Alessandra Magenta, and Maria Giulia Rizzo
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0301 basic medicine ,Chromatin Immunoprecipitation ,Euchromatin ,Transcription, Genetic ,Proliferation ,Mice, Transgenic ,Biology ,Cell cycle ,Response Elements ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,Animals ,Humans ,Promoter Regions, Genetic ,Cell Proliferation ,Nuclear lamina ,Transcription ,Oncology ,Genetics ,Regulation of gene expression ,Transcriptional activity ,CCAAT-Binding-Factor ,Cell growth ,High-Throughput Nucleotide Sequencing ,Lamin Type A ,humanities ,DNA-Binding Proteins ,Protein Transport ,030104 developmental biology ,CCAAT-Binding Factor ,Gene Expression Regulation ,Multiprotein Complexes ,Lamin ,Research Paper ,Protein Binding - Abstract
// Lucia Cicchillitti 1, * , Isabella Manni 1, * , Carmine Mancone 2, 3 , Giulia Regazzo 4 , Manuela Spagnuolo 4 , Tonino Alonzi 2 , Fabrizio Carlomosti 5, † , Maria Lucia Dell’Anna 6 , Giulia Dell’Omo 7 , Mauro Picardo 6 , Paolo Ciana 8 , Maurizio C. Capogrossi 5 , Marco Tripodi 2, 3 , Alessandra Magenta 5 , Maria Giulia Rizzo 4 , Aymone Gurtner 1, # , Giulia Piaggio 1, # 1 Department of Research, Advanced Diagnostics and Technological Innovation, SAFU Unit, Translational Research Area, Regina Elena National Cancer Institute, 00144 Rome, Italy 2 National Institute for Infectious Diseases L. Spallanzani, IRCCS, Department of Epidemiology and Preclinical Research, 00149 Rome, Italy 3 Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy 4 Department of Research, Advanced Diagnostics and Technological Innovation, Genomic and Epigenetic Unit, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy 5 Fondazione Luigi Maria Monti, Istituto Dermopatico dell’Immacolata-IRCCS, Laboratorio di Patologia Vascolare, 00167 Rome, Italy 6 Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, 00144 Rome, Italy 7 Department of Oncology and Hemato-Oncology and Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy 8 Center of Excellence on Neurodegenerative Diseases, Department of Oncology and Hemato-Oncology, University of Milan, 20133 Milan, Italy * These authors have contributed equally to this work # Co-last authors † In memory of Fabrizio Carlomosti who tragically passed away on October the 29 th 2015 Correspondence to: Giulia Piaggio, email: piaggio@ifo.it Aymone Gurtner, email: gurtner@ifo.it Keywords: transcription, proliferation, cell cycle, euchromatin, nuclear lamina Received: May 18, 2016 Accepted: October 10, 2016 Published: October 26, 2016 ABSTRACT Lamin A is a component of the nuclear matrix that also controls proliferation by largely unknown mechanisms. NF-Y is a ubiquitous protein involved in cell proliferation composed of three subunits (-YA -YB -YC) all required for the DNA binding and transactivation activity. To get clues on new NF-Y partner(s) we performed a mass spectrometry screening of proteins that co-precipitate with the regulatory subunit of the complex, NF-YA. By this screening we identified lamin A as a novel putative NF-Y interactor. Co-immunoprecipitation experiments and confocal analysis confirmed the interaction between the two endogenous proteins. Interestingly, this association occurs on euchromatin regions, too. ChIP experiments demonstrate lamin A enrichment in several promoter regions of cell cycle related genes in a NF-Y dependent manner. Gain and loss of function experiments reveal that lamin A counteracts NF-Y transcriptional activity. Taking advantage of a recently generated transgenic reporter mouse, called MITO-Luc, in which an NF-Y–dependent promoter controls luciferase expression, we demonstrate that lamin A counteracts NF-Y transcriptional activity not only in culture cells but also in living animals. Altogether, our data demonstrate the occurrence of lamin A/NF-Y interaction and suggest a possible role of this protein complex in regulation of NF-Y function in cell proliferation.
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- 2017
40. The Emerging Role of miR-200 Family in Cardiovascular Diseases
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Roberta Ciarapica, Maurizio C. Capogrossi, and Alessandra Magenta
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0301 basic medicine ,Cell type ,Physiology ,030204 cardiovascular system & hematology ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,insulin resistance ,microRNA ,medicine ,Animals ,Humans ,oxidative stress ,Transcription factor ,Chromosome 12 ,chemistry.chemical_classification ,Genetics ,Reactive oxygen species ,aging ,medicine.disease ,Cell biology ,cardiovascular diseases ,microRNAs ,030104 developmental biology ,chemistry ,Homeobox ,Cardiology and Cardiovascular Medicine ,Reperfusion injury ,Oxidative stress - Abstract
Recent studies have shown that reactive oxygen species increase the expression of miR-200 family (miR-200); however, little is known about this micro-RNA family in the cardiovascular system. In this Viewpoint, we provide evidence suggesting that miR-200 may be important in conditions that affect the heart and blood vessels. Oxidative stress plays a major role in cardiovascular physiopathology and some common conditions including aging, diabetes mellitus, atherosclerosis, and reperfusion injury induce reactive oxygen species (ROS). In 2011, it was first published that endothelial and skeletal muscle cells exposed to oxidative stress, in vitro and in vivo, exhibit a marked increase in miR-2001. Subsequently, ROS ability to induce miR-200 has been confirmed in many cell types. Furthermore, hypoxia enhances miR-429, an miR-200 member, and miR-429 targets HIF-1α (hypoxia-inducible factor-1α) and decreases its expression. Most miR-200 studies have been in the cancer field: miR-200 modulates epithelial–mesenchymal transition by targeting the transcription factors ZEB1 and ZEB2 (Zinc-finger E-box binding homeobox 1 and 2) and circulating miR-200 may represent clinically useful cancer biomarkers. In contrast, the role of miR-200 in CV diseases is still poorly investigated. MiRNAs are short (21–22 nucleotides) noncoding RNAs: their seed sequence (nucleotides 2–8 from the 5′ end) targets specific mRNAs and via this mechanism they inhibit translation and also may modulate mRNA stability. The miR-200 family is composed of 5 members clustered and expressed as 2 separate polycistronic pri-miRNA transcripts: in humans, miR-200c and miR-141 are on chromosome 12; miR-200a, miR-200b, and miR-429 are on chromosome 1. They are also identified by different seed sequences: subgroup I comprises miR-141 and miR-200a; subgroup II includes miR-200b, miR-200c, and miR-429. Because each miRNA can target numerous mRNAs and the 2 miR-200 subgroups have different seed sequences, the functional impact of miR-200 can be profound. The Figure shows the major miR-200c–activated …
- Published
- 2017
41. Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants
- Author
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Francesco Vasuri, Laura Graciotti, S. Pellegrini, Antonietta D'Errico, Grazia Pizza, Daniel Remondini, Marco D'Agostino, Alessandra Magenta, Elena Bellavista, Matteo Cescon, Maria Rita Rippo, Vincenzo Borelli, Enrico Tagliafico, Fiammetta Biondi, Raffaella Lazzarini, Alessandro Dazzi, Maurizio C. Capogrossi, Elena Tenedini, Gian Luca Grazi, Miriam Capri, Aurelia Santoro, Catia Lanzarini, Claudio Franceschi, Fabiola Olivieri, Maria Cristina Albertini, Antonio Domenico Procopio, Cristina Morsiani, Capri, Miriam, Olivieri, Fabiola, Lanzarini, Catia, Remondini, Daniel, Borelli, Vincenzo, Lazzarini, Raffaella, Graciotti, Laura, Albertini, Maria Cristina, Bellavista, Elena, Santoro, Aurelia, Biondi, Fiammetta, Tagliafico, Enrico, Tenedini, Elena, Morsiani, Cristina, Pizza, Grazia, Vasuri, Francesco, D'Errico, Antonietta, Dazzi, Alessandro, Pellegrini, Sara, Magenta, Alessandra, D'Agostino, Marco, Capogrossi, Maurizio C., Cescon, Matteo, Rippo, Maria Rita, Procopio, Antonio Domenico, Franceschi, Claudio, and Grazi, Gian Luca
- Subjects
0301 basic medicine ,Pathology ,Aging ,N-glycans ,elderly donors ,Age-mismatches ,Transcriptome ,GLT1 ,age-mismatches ,allograft ,microRNAs ,telomere length ,Allograft ,LS2_8 ,Age-mismatche ,Luciferases ,Aged, 80 and over ,Elderly donors ,MicroRNAs ,Telomere length ,Cell Biology ,Gene Expression Regulation, Developmental ,MicroRNA ,Middle Aged ,Telomere ,Immunohistochemistry ,Tissue Donors ,3. Good health ,mir-31 ,Excitatory Amino Acid Transporter 2 ,Liver ,N-glycan ,Original Article ,Transcriptional Elongation Factors ,Elderly donor ,Adult ,medicine.medical_specialty ,Adolescent ,Biology ,NO ,03 medical and health sciences ,Glutamate Plasma Membrane Transport Proteins ,Young Adult ,microRNA ,medicine ,Humans ,RNA, Messenger ,LS7_4 ,age‐mismatches ,Aged ,Messenger RNA ,Gene Expression Profiling ,Reproducibility of Results ,Original Articles ,N‐glycans ,Liver Transplantation ,Transplantation ,030104 developmental biology ,HEK293 Cells ,Liver function ,Biomarkers - Abstract
Summary To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12–92 years before transplants and in 11 biopsies after transplants with high donor–recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT–qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age-dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT–qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor–recipient extreme age-mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently ‘rejuvenated’ according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor–recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors.
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- 2017
42. Circulating miR-200c is up-regulated in paediatric patients with familial hypercholesterolaemia and correlates with miR-33a/b levels: Implication of a ZEB1-dependent mechanism
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Sandro Parrotto, Anna Montali, Alessandra Magenta, Daniele Avitabile, Eliana Martino, Cristina Zanoni, Luca Persico, Maurizio C. Capogrossi, Sara Beji, Marco D'Agostino, Fabio Maria Gangi, Francesco Martino, Lorenza Marchetti, Francesco Barillà, Mario Picozza, and Sara Sileno
- Subjects
0301 basic medicine ,miR-33 ,Senescence ,Blood Glucose ,Male ,medicine.medical_specialty ,Adolescent ,Inflammation ,MiR-200c ,Cardiovascular disease ,Hypercholesterolaemia ,MicroRNA ,MiR-33 ,Oxidative stress ,Paediatrics ,Zinc Finger E-box-Binding Homeobox 1 ,C-Reactive Protein ,Case-Control Studies ,Child ,Child, Preschool ,Female ,Humans ,Hyperlipoproteinemia Type II ,MicroRNAs ,Reactive Oxygen Species ,Up-Regulation ,Medicine (all) ,030204 cardiovascular system & hematology ,Biology ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Endothelial dysfunction ,Preschool ,hypercholesterolemia ,Cholesterol ,C-reactive protein ,Case-control study ,General Medicine ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,medicine.symptom - Abstract
Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating miR-33a/b expression levels were up-regulated in children with familial hypercholesterolaemia (FH). miR-33a/b control cholesterol homoeostasis and recently miR-33b has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the miR-200 family. Our previous studies showed that the ROS-dependent miR-200c up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating miR-200c was induced in FH children, and whether a correlation existed with miR-33a/b. Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and miR-200c levels were measured. We found that miR-200c was up-regulated in FH compared with HS (4.00 ± 0.48-fold increase, P
- Published
- 2017
43. Hypoxia-Induced miR-210 Modulates Tissue Response to Acute Peripheral Ischemia
- Author
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Germana Zaccagnini, Simona Greco, Maurizio C. Capogrossi, Valeria Di Stefano, Carlo Gaetano, Biagina Maimone, Alessandra Perfetti, Pasquale Fasanaro, and Fabio Martelli
- Subjects
Male ,Necrosis ,Physiology ,Clinical Biochemistry ,Gene Expression ,Apoptosis ,129 Strain ,Hindlimb ,Femoral artery ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Mice ,Ischemia ,General Environmental Science ,Mice, Knockout ,Forum Original Research Communications ,Medicine (all) ,Skeletal ,Cell Hypoxia ,medicine.anatomical_structure ,Acute Disease ,Systemic administration ,Muscle ,RNA Interference ,medicine.symptom ,Glycolysis ,medicine.medical_specialty ,Mice, 129 Strain ,Knockout ,Animals ,Cell Line ,MicroRNAs ,Muscle, Skeletal ,Oxidative Stress ,Cell Biology ,Molecular Biology ,medicine.artery ,medicine ,business.industry ,Skeletal muscle ,Hypoxia (medical) ,medicine.disease ,Surgery ,General Earth and Planetary Sciences ,business ,Oxidative stress - Abstract
Aims: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. Results: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66Shc-null mice displayed decreased tissue damage following ischemia. Innovation: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. Conclusions: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. Antioxid. Redox Signal. 21, 1177–1188.
- Published
- 2014
44. The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients
- Author
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Claudia Colussi, Maria Cristina Carena, Matteo Vecellio, Antonello Mai, Andreas M. Zeiher, Maurizio C. Capogrossi, Simona Nanni, Alessandra Rossini, Gianluca Sbardella, Giulio Pompilio, Fabio Martelli, Antonella Farsetti, Francesco Spallotta, Manuela Tilenni, Carlo Gaetano, Sabrina Castellano, Stefanie Dimmeler, Anja Derlet, Beatrice Bassetti, and Chiara Cencioni
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Cellular differentiation ,Histones ,Endocrinology ,LoCAMs ,Histone code ,Blotting, Western ,Cardiomyopathies ,Cell Differentiation ,Cell Proliferation ,CpG Islands ,DNA Methylation ,Diabetes Mellitus, Type 2 ,Diabetic Angiopathies ,Enzyme Activation ,Female ,Histone Acetyltransferases ,Humans ,Immunoprecipitation ,Malonates ,Mesenchymal Stromal Cells ,Middle Aged ,Myocytes, Cardiac ,Phosphorylation ,Promoter Regions, Genetic ,p300-CBP Transcription Factors ,Internal Medicine ,Medicine (all) ,Histone acetyltransferase modulators ,Blotting ,Diabetes ,Diabetes and Metabolism ,PCAF ,Epigenetics ,CpG site ,DNA methylation ,Western ,Cardiac ,Type 2 ,Biology ,Promoter Regions ,Histone H3 ,Genetic ,Diabetes Mellitus ,ddc:610 ,Myocytes ,Activator (genetics) ,Settore MED/13 - ENDOCRINOLOGIA ,Mesenchymal Stem Cells ,Molecular biology ,Acetylation ,Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE - Abstract
This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-? general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients. © 2014 by the American Diabetes Association.
- Published
- 2014
45. Nitric Oxide, Oxidative Stress, andp66ShcInterplay in Diabetic Endothelial Dysfunction
- Author
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Maurizio C. Capogrossi, Simona Greco, Alessandra Magenta, Carlo Gaetano, and Fabio Martelli
- Subjects
chemistry.chemical_classification ,Pathology ,medicine.medical_specialty ,Reactive oxygen species ,General Immunology and Microbiology ,business.industry ,Nitric Oxide Synthase Type III ,General Medicine ,Pharmacology ,medicine.disease ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Nitric oxide ,Endothelial stem cell ,chemistry.chemical_compound ,chemistry ,medicine ,Endothelial dysfunction ,Signal transduction ,business ,Intracellular ,Oxidative stress - Abstract
Increased oxidative stress and reduced nitric oxide (NO) bioavailability play a causal role in endothelial cell dysfunction occurring in the vasculature of diabetic patients. In this review, we summarized the molecular mechanisms underpinning diabetic endothelial and vascular dysfunction. In particular, we focused our attention on the complex interplay existing among NO, reactive oxygen species (ROS), and one crucial regulator of intracellular ROS production,p66Shcprotein.
- Published
- 2014
46. miR-200C Exhibits an Age-Dependent Increase in the Rat Heart and Modulates Cardiomyocyte Function
- Author
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Bruce D. Ziman, Cristina Florio, Maurizio C. Capogrossi, Edward G. Lakatta, Rostislav Byshkov, Kenta Tsutsui, and Alessandra Magenta
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medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Biophysics ,medicine ,Age dependent ,Rat heart ,Mir 200c ,Function (biology) - Published
- 2019
47. Transcriptional Profiling of Hmgb1-Induced Myocardial Repair Identifies a Key Role for Notch Signaling
- Author
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Giulio Pompilio, Matteo Antonio Russo, Anna Di Carlo, Federica Limana, Pasquale Fasanaro, Grazia Esposito, Fabio Martelli, Eleonora Foglio, Christine Voellenkle, Diego Arcelli, Daniele Avitabile, Antonia Germani, and Maurizio C. Capogrossi
- Subjects
Notch ,Angiogenesis ,Cells ,Cellular differentiation ,Myocardial Infarction ,Notch signaling pathway ,chemical and pharmacologic phenomena ,Animals, Cell Differentiation ,drug effects, Cell Proliferation ,drug effects, Cells ,Cultured, Female, Gene Expression Profiling, HMGB1 Protein ,administration /&/ dosage/pharma/cology, Heart ,drug effects, Mice, Mice ,Inbred C57BL, Myocardial Infarction ,metabolism/physiopathology, Myocardium ,metabolism, Myocytes ,Cardiac ,drug effects/metabolism, Receptors ,metabolism, Regeneration ,drug effects/genetics, Signal Transduction ,drug effects ,Biology ,Inbred C57BL ,HMGB1 ,Mice ,Vasculogenesis ,Receptors ,Drug Discovery ,Genetics ,Animals ,Regeneration ,Myocytes, Cardiac ,HMGB1 Protein ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Pharmacology ,Myocytes ,Cultured ,administration /&/ dosage/pharma/cology ,Receptors, Notch ,Gene Expression Profiling ,Myocardium ,Regeneration (biology) ,drug effects/genetics ,Cell Differentiation ,Heart ,Cell biology ,Mice, Inbred C57BL ,Gene expression profiling ,metabolism/physiopathology ,Immunology ,biology.protein ,Molecular Medicine ,Original Article ,Female ,Signal transduction ,drug effects/metabolism ,metabolism ,Signal Transduction - Abstract
Exogenous high-mobility group box 1 protein (HMGB1) administration to the mouse heart, during acute myocardial infarction (MI), results in cardiac regeneration via resident c-kit(+) cell (CPC) activation. Aim of the present study was to identify the molecular pathways involved in HMGB1-induced heart repair. Gene expression profiling was performed to identify differentially expressed genes in the infarcted and bordering regions of untreated and HMGB1-treated mouse hearts, 3 days after MI. Functional categorization of the transcripts, accomplished using Ingenuity Pathway Analysis software (IPA), revealed that genes involved in tissue regeneration, that is, cardiogenesis, vasculogenesis and angiogenesis, were present both in the infarcted area and in the peri-infarct zone; HMGB1 treatment further increased the expression of these genes. IPA revealed the involvement of Notch signaling pathways in HMGB1-treated hearts. Importantly, HMGB1 determined a 35 and 58% increase in cardiomyocytes and CPCs expressing Notch intracellular cytoplasmic domain, respectively. Further, Notch inhibition by systemic treatment with the γ-secretase inhibitor DAPT, which blocked the proteolytic activation of Notch receptors, reduced the number of CPCs, their proliferative fraction, and cardiomyogenic differentiation in HMGB1-treated infarcted hearts. The present study gives insight into the molecular processes involved in HMGB1-mediated cardiac regeneration and indicates Notch signaling as a key player.
- Published
- 2013
48. Detrimental Effect of Class-selective Histone Deacetylase Inhibitors during Tissue Regeneration following Hindlimb Ischemia
- Author
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Irene Bozzoni, Stefania Straino, Claudia Colussi, Antonella Farsetti, Matteo Vecellio, Francesco Spallotta, Jessica Rosati, Sergio Valente, Maurizio C. Capogrossi, Alfredo Pontecorvi, Antonello Mai, Silvia Tardivo, Julie Martone, Carlo Gaetano, and Simona Nanni
- Subjects
Male ,Epigenetics ,histone deacetylase inhibitors ,ischemia ,muscle regeneration ,nitric oxide ,protein phosphatase 2A ,animal structures ,Time Factors ,Pyridines ,viruses ,Ischemia ,Nitric Oxide Synthase Type I ,Hindlimb ,Pharmacology ,Hydroxamic Acids ,Nitric Oxide ,complex mixtures ,Biochemistry ,Histone Deacetylases ,Dystrophin ,Mice ,fluids and secretions ,Fibrosis ,mental disorders ,medicine ,Animals ,Regeneration ,Pyrroles ,Protein Phosphatase 2 ,Muscle, Skeletal ,Molecular Biology ,biology ,Regeneration (biology) ,Cell Biology ,medicine.disease ,Molecular biology ,HDAC1 ,Histone Deacetylase Inhibitors ,Protein Phosphatase 2A ,Histone ,Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,Benzamides ,biology.protein ,Histone deacetylase ,Muscle Regeneration - Abstract
Histone deacetylase inhibitors (DIs) are promising drugs for the treatment of several pathologies including ischemic and failing heart where they demonstrated efficacy. However, adverse side effects and cardiotoxicity have also been reported. Remarkably, no information is available about the effect of DIs during tissue regeneration following acute peripheral ischemia. In this study, mice made ischemic by femoral artery excision were injected with the DIs MS275 and MC1568, selective for class I and IIa histone deacetylases (HDACs), respectively. In untreated mice, soon after damage, class IIa HDAC phosphorylation and nuclear export occurred, paralleled by dystrophin and neuronal nitric-oxide synthase (nNOS) down-regulation and decreased protein phosphatase 2A activity. Between 14 and 21 days after ischemia, dystrophin and nNOS levels recovered, and class IIa HDACs relocalized to the nucleus. In this condition, the MC1568 compound increased the number of newly formed muscle fibers but delayed their terminal differentiation, whereas MS275 abolished the early onset of the regeneration process determining atrophy and fibrosis. The selective DIs had differential effects on the vascular compartment: MC1568 increased arteriogenesis whereas MS275 inhibited it. Capillarogenesis did not change. Chromatin immunoprecipitations revealed that class IIa HDAC complexes bind promoters of proliferation-associated genes and of class I HDAC1 and 2, highlighting a hierarchical control between class II and I HDACs during tissue regeneration. Our findings indicate that class-selective DIs interfere with normal mouse ischemic hindlimb regeneration and suggest that their use could be limited by alteration of the regeneration process in peripheral ischemic tissues.
- Published
- 2013
49. Patient profile modulates cardiac c-kit+ progenitor cell availability and amplification potential
- Author
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Marco Agrifoglio, Maurizio C. Capogrossi, Elisa Gambini, Beatrice Bassetti, Francesco Alamanni, Giulio Pompilio, Luca Persico, Maurizio Pesce, and Antonio Gambini
- Subjects
Male ,Cell ,Cell Culture Techniques ,Biology ,Stem cell marker ,Flow cytometry ,Risk Factors ,Physiology (medical) ,medicine ,Humans ,Heart Atria ,Progenitor cell ,Aged ,medicine.diagnostic_test ,Multipotent Stem Cells ,Myocardium ,Stem Cells ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,General Medicine ,Middle Aged ,Flow Cytometry ,Immunohistochemistry ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Cardiovascular Diseases ,Cell culture ,Immunology ,Cancer research ,biology.protein ,Female ,Antibody ,Homeostasis - Abstract
Human c-kit + cardiac progenitor cells (CPCs) are multipotent and may be used for cardiac repair. The effect of cardiovascular risk factors and medications on CPCs isolation efficiency, c-kit stem cell marker expression, and ex vivo proliferative potential is unknown and was examined in the present work. Cells from human right atrial appendages (n = 50) were expanded in culture; after ∼16 days (T0), it was established the percentage of CPCs and c-kit protein mean fluorescence intensity (MFI) by fluorescence activated cell sorting (FACS). Thereafter, CPCs were isolated by high throughput sorting; after culturing for 4 passages CPCs-derived cells were re-analyzed to assess c-kit + cell percentage and enrichment vs T0. The association between 19 demographic and clinical variables to CPCs number and MFI at T0, and CPCs enrichment at P4, was determined by multiple linear regression analysis with stepwise selection procedure. The results revealed that (1) at T0, the number of isolated CPCs directly correlated to β-blocker treatment; (2) at T0, c-kit protein expression directly correlated to pulmonary hypertension (PH); (3) at P4, CPC's enrichment inversely correlated to smoke, atrial fibrillation (AF), a history of myocardial infarction, whereas it directly correlated to PH and statins. Patient clinical profile and medications differently modulate CPCs isolation and amplification potential ex vivo. These results may provide new insights for the understanding of cardiac homeostasis and suggest both limitations and possible enhancing strategies for the therapeutic use of cardiac-resident progenitor cells.
- Published
- 2012
50. The role of oncogenic Ras in human skin tumorigenesis depends on clonogenic potential of the founding keratinocytes
- Author
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Sergio Bondanza, Riccardo Maurelli, Maurizio C. Capogrossi, Anna Lisa Severi, Giuseppe Mesiti, Lavinia Tinaburri, Claudia Scarponi, Fabio Maria Gangi, Liliana Guerra, Elena Dellambra, and Cristina Albanesi
- Subjects
Keratinocytes ,0301 basic medicine ,Senescence ,Skin Neoplasms ,Nude ,Clonogenic potential ,Primary human keratinocyte ,Ras ,Tumorigenesis ,Animals ,Cell Aging ,Cell Proliferation ,Cell Transformation, Neoplastic ,Coculture Techniques ,Humans ,Mice ,Mice, Nude ,NIH 3T3 Cells ,Neoplasm Transplantation ,Neoplastic Stem Cells ,Proto-Oncogene Proteins p21(ras) ,Signal Transduction ,Cell Biology ,Biology ,Cell Transformation ,medicine.disease_cause ,03 medical and health sciences ,medicine ,Telomerase reverse transcriptase ,Clonogenic assay ,Cellular Senescence ,Neoplastic ,Molecular biology ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Stem cell ,Carcinogenesis ,Keratinocyte ,Cell aging - Abstract
The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras-V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying- or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Moreover, only transduced cultures originating from cultures bearing stem cells induce tumors in nude mice. Our findings demonstrate that the Ras overexpression outcome depends on the clonogenic potential of the recipient keratinocyte and that only the stem cell compartment is competent to initiate tumorigenesis.
- Published
- 2016
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