19 results on '"Kostina, Aleksandra"'
Search Results
2. ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development.
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Kostina A, Lewis-Israeli YR, Abdelhamid M, Gabalski MA, Kiselev A, Volmert BD, Lankerd H, Huang AR, Wasserman AH, Lydic T, Chan C, Park S, Olomu I, and Aguirre A
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- Humans, Mice, Animals, Endoplasmic Reticulum Stress physiology, Protein Serine-Threonine Kinases metabolism, Organoids metabolism, Lipids, Diabetes Mellitus, Heart Defects, Congenital pathology, Cardiomyopathies
- Abstract
Congenital heart defects are the most prevalent human birth defects, and their incidence is exacerbated by maternal health conditions, such as diabetes during the first trimester (pregestational diabetes). Our understanding of the pathology of these disorders is hindered by a lack of human models and the inaccessibility of embryonic tissue. Using an advanced human heart organoid system, we simulated embryonic heart development under pregestational diabetes-like conditions. These organoids developed pathophysiological features observed in mouse and human studies before, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed cardiac cell-type-specific dysfunction affecting epicardial and cardiomyocyte populations and alterations in the endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidemia was linked to fatty acid desaturase 2 mRNA decay dependent on IRE1-RIDD signaling. Targeting IRE1 or restoring lipid levels partially reversed the effects of pregestational diabetes, offering potential preventive and therapeutic strategies in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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3. Human heart organoids: current applications and future perspectives.
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Kostina A, Volmert B, and Aguirre A
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- Humans, Organoids, Brain
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- 2024
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4. A patterned human primitive heart organoid model generated by pluripotent stem cell self-organization.
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Volmert B, Kiselev A, Juhong A, Wang F, Riggs A, Kostina A, O'Hern C, Muniyandi P, Wasserman A, Huang A, Lewis-Israeli Y, Panda V, Bhattacharya S, Lauver A, Park S, Qiu Z, Zhou C, and Aguirre A
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- Pregnancy, Humans, Female, Organoids metabolism, Heart, Cell Differentiation physiology, Induced Pluripotent Stem Cells metabolism, Pluripotent Stem Cells, Heart Diseases metabolism
- Abstract
Pluripotent stem cell-derived organoids can recapitulate significant features of organ development in vitro. We hypothesized that creating human heart organoids by mimicking aspects of in utero gestation (e.g., addition of metabolic and hormonal factors) would lead to higher physiological and anatomical relevance. We find that heart organoids produced using this self-organization-driven developmental induction strategy are remarkably similar transcriptionally and morphologically to age-matched human embryonic hearts. We also show that they recapitulate several aspects of cardiac development, including large atrial and ventricular chambers, proepicardial organ formation, and retinoic acid-mediated anterior-posterior patterning, mimicking the developmental processes found in the post-heart tube stage primitive heart. Moreover, we provide proof-of-concept demonstration of the value of this system for disease modeling by exploring the effects of ondansetron, a drug administered to pregnant women and associated with congenital heart defects. These findings constitute a significant technical advance for synthetic heart development and provide a powerful tool for cardiac disease modeling., (© 2023. The Author(s).)
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- 2023
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5. ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes.
- Author
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Kostina A, Lewis-Israeli YR, Abdelhamid M, Gabalski MA, Volmert BD, Lankerd H, Huang AR, Wasserman AH, Lydic T, Chan C, Olomu I, and Aguirre A
- Abstract
Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.
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- 2023
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6. Context-Specific Osteogenic Potential of Mesenchymal Stem Cells.
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Kostina A, Lobov A, Semenova D, Kiselev A, Klausen P, and Malashicheva A
- Abstract
Despite the great progress in the field of bone tissue regeneration, the early initiating mechanisms of osteogenic differentiation are not well understood. Cells capable of osteogenic transformation vary from mesenchymal stem cells of various origins to mural cells of vessels. The mechanisms of pathological calcification are thought to be similar to those of bone formation. Notch signaling has been shown to play an important role in osteogenic differentiation, as well as in pathological calcification. Nevertheless, despite its known tissue- and context-specificity, the information about its role in the osteogenic differentiation of different cells is still limited. We compared mesenchymal stem cells from adipogenic tissue (MSCs) and interstitial cells from the aortic valve (VICs) by their ability to undergo Notch-dependent osteogenic differentiation. We showed differences between the two types of cells in their ability to activate the expression of proosteogenic genes RUNX2 , BMP2 , BMP4 , DLX2 , BGLAP , SPRY , IBSP , and SPP1 in response to Notch activation. Untargeted metabolomic profiling also confirms differences between MSCs and VICs in their osteogenic state. Analysis of the activity of RUNX2 and SPP1 promoters shows fine-tuned dose-dependency in response to Notch induction and suggests a direct link between the level of Notch activation, and the proostogenic gene expression and corresponding osteogenic induction. Our data suggest that osteogenic differentiation is a context-dependent process and the outcome of it could be cell-type dependent.
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- 2021
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7. Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease.
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Theodoris CV, Zhou P, Liu L, Zhang Y, Nishino T, Huang Y, Kostina A, Ranade SS, Gifford CA, Uspenskiy V, Malashicheva A, Ding S, and Srivastava D
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- Algorithms, Animals, Aortic Valve drug effects, Aortic Valve metabolism, Aortic Valve physiopathology, Aortic Valve Disease genetics, Aortic Valve Disease physiopathology, Aortic Valve Stenosis genetics, Aortic Valve Stenosis physiopathology, Calcinosis genetics, Calcinosis physiopathology, Disease Models, Animal, Drug Discovery, Drug Evaluation, Preclinical, Gene Expression Regulation drug effects, Haploinsufficiency, Humans, Induced Pluripotent Stem Cells, Mice, Inbred C57BL, RNA-Seq, Receptor, Notch1 genetics, Small Molecule Libraries, Mice, Aortic Valve pathology, Aortic Valve Disease drug therapy, Aortic Valve Stenosis drug therapy, Calcinosis drug therapy, Gene Regulatory Networks drug effects, Machine Learning, Nitriles pharmacology, Nitriles therapeutic use, Thiazoles pharmacology, Thiazoles therapeutic use
- Abstract
Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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- 2021
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8. Dysregulation of Notch signaling in cardiac mesenchymal cells of patients with tetralogy of Fallot.
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Kozyrev I, Dokshin P, Kostina A, Kiselev A, Ignatieva E, Golovkin A, Pervunina T, Grekhov E, Gordeev M, Kostareva A, and Malashicheva A
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- Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Cycle Proteins metabolism, Cell Differentiation, Cell Proliferation, Female, Gene Expression Profiling, Gene Expression Regulation, Heart physiopathology, Heart Ventricles metabolism, Humans, Hypoxia, Immunophenotyping, Infant, Infant, Newborn, Male, Mutation, Signal Transduction, Transcription Factor HES-1 metabolism, Heart Septal Defects, Ventricular metabolism, Mesenchymal Stem Cells cytology, Myocardium metabolism, Receptors, Notch metabolism, Tetralogy of Fallot metabolism
- Abstract
Background: Tetralogy of Fallot (TF) is a severe congenital defect of heart development. Fine-tuned sequential activation of Notch signaling genes is responsible for proper heart chamber development. Mutations in Notch genes have been associated with TF. The aim of this study was to analyze the activity of the Notch pathway in cardiac mesenchymal cells derived from ventricular tissue of TF patients., Methods: Cardiac mesenchymal cells were isolated from 42 TF patients and from 14 patients with ventricular septal defects (VSDs), used as a comparison group. The Notch pathway was analyzed by estimating the expression of Notch-related genes by qPCR. Differentiation and proliferation capacity of the cells was estimated., Results: The TF-derived cells demonstrated a dysregulated pattern of Notch-related gene expression comparing to VSD-derived cells. Correlation of Notch signaling activation level by HEY1/HES1 expression level with proliferation and cardiogenic-like differentiation of cardiac mesenchymal cells was observed but not with clinical parameters nor with the age of the patients., Conclusions: The data suggest a contribution of dysregulated Notch signaling to the pathogenesis of tetralogy of Fallot and importance of Notch signaling level for the functional state of cardiac mesenchymal cells, which could be critical considering these cells for potential cell therapy approaches.
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- 2020
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9. Insights Image for "Dysregulation of Notch signaling in cardiac mesenchymal cells of patients with Tetralogy of Fallot".
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Kozyrev I, Dokshin P, Kostina A, Kiselev A, Ignatieva E, Golovkin A, Pervunina T, Grekhov E, Gordeev M, Kostareva A, and Malashicheva A
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- Humans, Models, Biological, Models, Cardiovascular, Receptors, Notch metabolism, Signal Transduction, Gene Expression Profiling, Gene Expression Regulation, Heart physiopathology, Mesenchymal Stem Cells metabolism, Tetralogy of Fallot genetics
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- 2020
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10. Generation of two iPSC lines (FAMRCi007-A and FAMRCi007-B) from patient with Emery-Dreifuss muscular dystrophy and heart rhythm abnormalities carrying genetic variant LMNA p.Arg249Gln.
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Perepelina K, Kostina A, Klauzen P, Khudiakov A, Rabino M, Crasto S, Zlotina A, Fomicheva Y, Sergushichev A, Oganesian M, Dmitriev A, Kostareva A, Di Pasquale E, and Malashicheva A
- Abstract
Human iPSC lines were generated from peripheral blood mononuclear cells of patient carrying LMNA mutation associated with Emery-Dreifuss muscular dystrophy accompanied by atrioventricular block and paroxysmal atrial fibrillation. Reprogramming factors OCT4, KLF4, SOX2, CMYC were delivered using Sendai virus transduction. iPSCs were characterized in order to prove the pluripotency markers expression, normal karyotype, ability to differentiate into three embryonic germ layers. Generated iPSC lines would be useful model to investigate disease development associated with genetic variants in LMNA gene., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)
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- 2020
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11. Corrigendum to "Notch signaling in the pathogenesis of thoracic aortic aneurysms: A bridge between embryonic and adult states" [Biochim. Biophys. Acta Mol. Basis Dis. 1866 (3) (Mar 1 2020) 165631].
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Malashicheva A, Kostina A, Kostareva A, Irtyuga O, and Uspensky V
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- 2020
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12. Notch signaling in the pathogenesis of thoracic aortic aneurysms: A bridge between embryonic and adult states.
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Malashicheva A, Kostina A, Kostareva A, Irtyuga O, Gordeev M, and Uspensky V
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- Adult, Aorta metabolism, Aortic Aneurysm, Thoracic genetics, Aortic Aneurysm, Thoracic metabolism, Cell Differentiation, Humans, Receptors, Notch genetics, Signal Transduction, Aorta embryology, Aortic Aneurysm, Thoracic pathology, Gene Expression Regulation, Developmental, Receptors, Notch metabolism
- Abstract
Aneurysms of the thoracic aorta are a "silent killer" with no evident clinical signs until the fatal outcome. Molecular and genetic bases of thoracic aortic aneurysms mainly include transforming growth factor beta signaling, smooth muscle contractile units and metabolism genes, and extracellular matrix genes. In recent studies, a role of Notch signaling, among other pathways, has emerged in disease pathogenesis. Notch is a highly conserved signaling pathway that regulates the development and differentiation of many types of tissues and influences major cellular processes such as cell proliferation, differentiation and apoptosis. Mutations in several Notch signaling components have been associated with a number of heart defects, demonstrating an essential role of Notch signaling both in cardiovascular system development and its maintenance during postnatal life. This review discusses the role of Notch signaling in the pathogenesis of thoracic aortic aneurysms considering development and maintenance of the aortic root and how developmental regulations by Notch signaling may influence thoracic aortic aneurysms., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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13. Dose-dependent mechanism of Notch action in promoting osteogenic differentiation of mesenchymal stem cells.
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Semenova D, Bogdanova M, Kostina A, Golovkin A, Kostareva A, and Malashicheva A
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- Cell Communication, Cells, Cultured, Coculture Techniques, Humans, Jagged-1 Protein genetics, Jagged-1 Protein physiology, Lentivirus genetics, Receptors, Notch genetics, Transduction, Genetic, Mesenchymal Stem Cells physiology, Osteogenesis genetics, Receptors, Notch physiology
- Abstract
Osteogenic differentiation is a tightly regulated process realized by progenitor cell osteoblasts. Notch signaling pathway plays a critical role in skeletal development and bone remodeling. Controversial data exist regarding the role of Notch activation in promoting or preventing osteogenic differentiation. This study aims to investigate the effect of several Notch components and their dosage on osteogenic differentiation of mesenchymal stem cells of adipose tissue. Osteogenic differentiation was induced in the presence of either of Notch components (NICD, Jag1, Dll1, Dll4) dosed by lentiviral transduction. We show that osteogenic differentiation was increased by NICD and Jag1 transduction in a dose-dependent manner; however, a high dosage of both NICD and Jag1 decreased the efficiency of osteogenic differentiation. NICD dose-dependently increased activity of the CSL luciferase reporter but a high dosage of NICD caused a decrease in the activity of the reporter. A high dosage of both Notch components NICD and Jag1 induced apoptosis. In co-culture experiments where only half of the cells were transduced with either NICD or Jag1, only NICD increased osteogenic differentiation according to the dosage, while Jag1-transduced cells differentiated almost equally independently on dosage. In conclusion, activation of Notch promotes osteogenic differentiation in a tissue-specific dose-dependent manner; both NICD and Jag1 are able to increase osteogenic potential but at moderate doses only and a high dosage of Notch activation is detrimental to osteogenic differentiation. This result might be especially important when considering possibilities of using Notch activation to promote osteogenesis in clinical applications to bone repair.
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- 2020
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14. The Notch pathway: a novel therapeutic target for cardiovascular diseases?
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Aquila G, Kostina A, Vieceli Dalla Sega F, Shlyakhto E, Kostareva A, Marracino L, Ferrari R, Rizzo P, and Malaschicheva A
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- Animals, Aortic Aneurysm mortality, Aortic Aneurysm physiopathology, Aortic Valve physiopathology, Aortic Valve Stenosis mortality, Aortic Valve Stenosis physiopathology, Calcinosis mortality, Calcinosis physiopathology, Heart Failure mortality, Heart Failure physiopathology, Humans, Receptors, Notch metabolism, Aortic Aneurysm therapy, Aortic Valve pathology, Aortic Valve Stenosis therapy, Calcinosis therapy, Heart Failure therapy
- Abstract
Introduction : The Notch pathway is involved in determining cell fate during development and postnatally in continuously renewing tissues, such as the endothelium, the epithelium, and in the stem cells pool. The dysregulation of the Notch pathway is one of the causes of limited response, or resistance, to available cancer treatments and novel therapeutic strategies based on Notch inhibition are being investigated in preclinical and clinical studies in oncology. A large body of evidence now shows that the dysregulation of the Notch pathway is also involved in the pathophysiology of cardiovascular diseases (CVDs). Areas covered : This review discusses the molecular mechanisms involving Notch which underlie heart failure, aortic valve calcification, and aortic aneurysm. Expert opinion : Despite the existence of preventive, pharmacological and surgical interventions approaches, CVDs are the first causes of mortality worldwide. The Notch pathway is becoming increasingly recognized as being involved in heart failure, aortic aneurysm and aortic valve calcification, which are among the most common global causes of mortality due to CVDs. As already shown in cancer, the dissection of the biological processes and molecular mechanisms involving Notch should pave the way for new strategies to prevent and cure these diseases.
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- 2019
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15. Human aortic endothelial cells have osteogenic Notch-dependent properties in co-culture with aortic smooth muscle cells.
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Kostina A, Semenova D, Kostina D, Uspensky V, Kostareva A, and Malashicheva A
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- Cells, Cultured, Coculture Techniques, Gene Expression Profiling, Humans, Signal Transduction, Aorta cytology, Calcinosis, Endothelial Cells cytology, Endothelial Cells metabolism, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle metabolism, Osteogenesis, Receptors, Notch metabolism
- Abstract
Cardiovascular calcification is one of the leading reasons of morbidity and mortality in Western countries and has many similarities to osteogenesis. The role of smooth muscle calcific transformation is well established for atherogenic lesions, but mechanisms driving initial stages of proosteogenic cell fate commitment in big vessels remain poorly understood. The role of endothelial and underlying interstitial cell interaction in driving cellular decisions is emerging from recent studies. The aim of this study was to analyze co-culture of endothelial and smooth muscle cells in vitro in acquiring proosteogenic phenotype. We co-cultured human aortic endothelial cells (EC) and human aortic smooth muscle cells (SMC) and analyzed osteogenic phenotype by ALP staining and proosteogenic gene expression by qPCR in co-cultures and in separate cellular types after magnetic CD31-sorting. In EC and SMC co-cultures osteogenic phenotype was induced as well as activated expression of RUNX2, POSTIN, BMP2/4, SOX5, COL1A SMC; co-culture of EC with SMC induced NOTCH1, NOTCH3, NOTCH4 and HEY1 expression; Notch activation by lentiviral activated Notch intracellular domain induced expression of RUNX2, OPN, POSTIN in SMC; NOTCH1 and NOTCH3 and HEY1 were selectively induced in EC during co-culture. We conclude that endothelial cells are capable of driving smooth muscle calcification via cell-cell contact and activation of Notch signaling., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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16. Inflammation and Mechanical Stress Stimulate Osteogenic Differentiation of Human Aortic Valve Interstitial Cells.
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Bogdanova M, Kostina A, Zihlavnikova Enayati K, Zabirnyk A, Malashicheva A, Stensløkken KO, Sullivan GJ, Kaljusto ML, Kvitting JP, Kostareva A, Vaage J, and Rutkovskiy A
- Abstract
Background: Aortic valve calcification is an active proliferative process, where interstitial cells of the valve transform into either myofibroblasts or osteoblast-like cells causing valve deformation, thickening of cusps and finally stenosis. This process may be triggered by several factors including inflammation, mechanical stress or interaction of cells with certain components of extracellular matrix. The matrix is different on the two sides of the valve leaflets. We hypothesize that inflammation and mechanical stress stimulate osteogenic differentiation of human aortic valve interstitial cells (VICs) and this may depend on the side of the leaflet. Methods: Interstitial cells isolated from healthy and calcified human aortic valves were cultured on collagen or elastin coated plates with flexible bottoms, simulating the matrix on the aortic and ventricular side of the valve leaflets, respectively. The cells were subjected to 10% stretch at 1 Hz (FlexCell bioreactor) or treated with 0.1 μg/ml lipopolysaccharide, or both during 24 h. Gene expression of myofibroblast- and osteoblast-specific genes was analyzed by qPCR. VICs cultured in presence of osteogenic medium together with lipopolysaccharide, 10% stretch or both for 14 days were stained for calcification using Alizarin Red. Results: Treatment with lipopolysaccharide increased expression of osteogenic gene bone morphogenetic protein 2 (BMP2) (5-fold increase from control; p = 0.02) and decreased expression of mRNA of myofibroblastic markers: α-smooth muscle actin (ACTA2) (50% reduction from control; p = 0.0006) and calponin (CNN1) (80% reduction from control; p = 0.0001) when cells from calcified valves were cultured on collagen, but not on elastin. Mechanical stretch of VICs cultured on collagen augmented the effect of lipopolysaccharide. Expression of periostin (POSTN) was inhibited in cells from calcified donors after treatment with lipopolysaccharide on collagen (70% reduction from control, p = 0.001), but not on elastin. Lipopolysaccharide and stretch both enhanced the pro-calcific effect of osteogenic medium, further increasing the effect when combined for cells cultured on collagen, but not on elastin. Conclusion: Inflammation and mechanical stress trigger expression of osteogenic genes in VICs in a side-specific manner, while inhibiting the myofibroblastic pathway. Stretch and lipopolysaccharide synergistically increase calcification.
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- 2018
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17. Notch, BMP and WNT/β-catenin network is impaired in endothelial cells of the patients with thoracic aortic aneurysm.
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Kostina A, Bjork H, Ignatieva E, Irtyuga O, Uspensky V, Semenova D, Maleki S, Tomilin A, Moiseeva O, Franco-Cereceda A, Gordeev M, Faggian G, Kostareva A, Eriksson P, and Malashicheva A
- Subjects
- Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Aorta, Thoracic pathology, Aorta, Thoracic physiopathology, Aortic Aneurysm, Thoracic genetics, Aortic Aneurysm, Thoracic pathology, Aortic Aneurysm, Thoracic physiopathology, Bone Morphogenetic Protein 2 genetics, Calcium-Binding Proteins, Cells, Cultured, Endothelial Cells pathology, Female, Gene Expression Regulation, Humans, Intercellular Signaling Peptides and Proteins metabolism, Male, Mechanotransduction, Cellular, Middle Aged, Receptors, Notch genetics, Regional Blood Flow, Snail Family Transcription Factors metabolism, Stress, Mechanical, Aorta, Thoracic metabolism, Aortic Aneurysm, Thoracic metabolism, Bone Morphogenetic Protein 2 metabolism, Endothelial Cells metabolism, Receptors, Notch metabolism, Wnt Signaling Pathway genetics
- Abstract
Cellular and molecular mechanisms of thoracic aortic aneurysm are still not clear and therapeutic approaches are mostly absent. The role of endothelial cells in aortic wall integrity is emerging from recent studies. Although Notch pathway ensures endothelial development and integrity, and NOTCH1 mutations have been associated with thoracic aortic aneurysms, the role of this pathway in aneurysm remains elusive. The purpose of the present work was to study functions of Notch genes in endothelial cells of patients with sporadic thoracic aortic aneurysm. Aortic endothelial cells were isolated from aortic tissue of patients with thoracic aortic aneurysm and healthy donors. Gene expression of Notch and related BMP and WNT/β-catenin pathways was estimated by qPCR; WNT/β-catenin signaling was studied by TCF-luciferase reporter. To study the stress-response the cells were subjected to laminar shear stress and the expression of corresponding genes was estimated by qPCR. Analyses of mRNA expression of Notch genes, Notch target genes and Notch related pathways showed that endothelial cells of aneurysm patients have dysregulated Notch/BMP/WNT pathways compared to donor cells. Activity of Wnt pathway was significantly elevated in endothelial cells of the patients. Cells from patients had attenuated activation of DLL4, SNAIL1, DKK1 and BMP2 in response to shear stress. In conclusion endothelial cells of the patients with thoracic aortic aneurysm have dysregulated Notch, BMP and WNT/β-catenin related signaling. Shear stress-response and cross-talk between Notch and Wnt pathways that normally ensures aortic integrity and resistance of endothelial cells to stress is impaired in aneurysmal patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)
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- 2018
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18. Notch-dependent EMT is attenuated in patients with aortic aneurysm and bicuspid aortic valve.
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Kostina AS, Uspensky VЕ, Irtyuga OB, Ignatieva EV, Freylikhman O, Gavriliuk ND, Moiseeva OM, Zhuk S, Tomilin A, Kostareva АА, and Malashicheva AB
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- Adult, Aortic Aneurysm pathology, Aortic Valve metabolism, Aortic Valve pathology, Bicuspid Aortic Valve Disease, Endothelium, Vascular pathology, Female, Heart Valve Diseases pathology, Humans, Male, Middle Aged, Aortic Aneurysm metabolism, Aortic Valve abnormalities, Endothelium, Vascular metabolism, Heart Valve Diseases metabolism, Receptors, Notch metabolism, Signal Transduction
- Abstract
Bicuspid aortic valve is the most common congenital heart malformation and the reasons for the aortopathies associated with bicuspid aortic valve remain unclear. NOTCH1 mutations are associated with bicuspid aortic valve and have been found in individuals with various left ventricular outflow tract abnormalities. Notch is a key signaling during cardiac valve formation that promotes the endothelial-to-mesenchymal transition. We address the role of Notch signaling in human aortic endothelial cells from patients with bicuspid aortic valve and aortic aneurysm. Aortic endothelial cells were isolated from tissue fragments of bicuspid aortic valve-associated thoracic aortic aneurysm patients and from healthy donors. Endothelial-to-mesenchymal transition was induced by activation of Notch signaling. Effectiveness of the transition was estimated by loss of endothelial and gain of mesenchymal markers by immunocytochemistry and qPCR. We show that aortic endothelial cells from the patients with aortic aneurysm and bicuspid aortic valve have down regulated Notch signaling and fail to activate Notch-dependent endothelial-to-mesenchymal transition in response to its stimulation by different Notch ligands. Our findings support the idea that bicuspid aortic valve and associated aortic aneurysm is associated with dysregulation of the entire Notch signaling pathway independently on the specific gene mutation., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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19. Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms.
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Malashicheva A, Kostina D, Kostina A, Irtyuga O, Voronkina I, Smagina L, Ignatieva E, Gavriliuk N, Uspensky V, Moiseeva O, Vaage J, and Kostareva A
- Abstract
Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.
- Published
- 2016
- Full Text
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