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2. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype

Author

Lecce, Laura, Xu, Yang, V'Gangula, Bhargavi, Chandel, Nirupama, Pothula, Venu, Caudrillier, Axelle, Santini, Maria Paola, d'Escamard, Valentina, Ceholski, Delaine K., Gorski, Przemek A., Ma, Lijiang, Koplev, Simon, Bjorklund, Martin Maeng, Bjorkegren, Johan L.M., Boehm, Manfred, Bentzon, Jacob Fog, Fuster, Valentin, Kim, Ha Won, Weintraub, Neal L., Baker, Andrew H., Bernstein, Emily, and Kovacic, Jason C.

Subjects
Atherosclerotic plaque -- Development and progression -- Genetic aspects, Cardiovascular research, Stem cells -- Genetic aspects -- Health aspects, Cell differentiation -- Genetic aspects -- Health aspects, Epithelial cells -- Health aspects -- Genetic aspects, Phenotype -- Research, Health care industry
Abstract

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class Ila HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class Ila HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease., Introduction Endothelial-mesenchymal transition (EndMT) is an essential process during cardiac development, contributing to cardiac valve formation and the stabilization of new vasculature in the developing embryo (1, 2). EndMT also [...]

Published
2021
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5. Correction: Corrigendum: Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability

Author

Evrard, Solene M., Lecce, Laura, Michelis, Katherine C., Nomura-Kitabayashi, Aya, Pandey, Gaurav, Purushothaman, K-Raman, d’Escamard, Valentina, Li, Jennifer R., Hadri, Lahouaria, Fujitani, Kenji, Moreno, Pedro R., Benard, Ludovic, Rimmele, Pauline, Cohain, Ariella, Mecham, Brigham, Randolph, Gwendalyn J., Nabel, Elizabeth G., Hajjar, Roger, Fuster, Valentin, Boehm, Manfred, and Kovacic, Jason C.

Published
2017
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8. A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis

Author

Dunn, Louise L., Simpson, Philippa J.L., Prosser, Hamish C., Lecce, Laura, Yuen, Gloria S.C., Buckle, Andrew, Sieveking, Daniel P., Vanags, Laura Z., Lim, Patrick R., Chow, Renee W.Y., Lam, Yuen Ting, Clayton, Zoe, Bao, Shisan, Davies, Michael J., Stadler, Nadina, Celermajer, David S., Stocker, Roland, Bursill, Christina A., Cooke, John P., and Ng, Martin K.C.

Subjects
Diabetes -- Physiological aspects -- Genetic aspects, Neovascularization -- Genetic aspects, Thioredoxin -- Physiological aspects -- Genetic aspects, Health
Abstract

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes. DOI: 10.2337/db13-0417, A major part of the morbidity and mortality of diabetes arises from its vascular complications, of which impaired angiogenesis is an important feature (1). Patients with diabetes have impaired collateral [...]

Published
2014
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10. Androgens Stimulate EPC-Mediated Neovascularization and Are Associated with Increased Coronary Collateralization

Author

Lam, Yuen Ting, primary, Hsu, Chi-Jen, additional, Simpson, Philippa J L, additional, Dunn, Louise L, additional, Chow, Renee W, additional, Chan, Kim H, additional, Yong, Andy S C, additional, Yu, Young, additional, Sieveking, Daniel P, additional, Lecce, Laura, additional, Yuan, Jun, additional, Celermajer, David S, additional, Wise, Steven G, additional, and Ng, Martin K C, additional

Published
2020
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12. Fenofibrate Rescues Diabetes-Related Impairment of Ischemia-Mediated Angiogenesis by PPARα-Independent Modulation of Thioredoxin-Interacting Protein

Author

Yuan, Jun, primary, Tan, Joanne T.M., additional, Rajamani, Kushwin, additional, Solly, Emma L., additional, King, Emily J., additional, Lecce, Laura, additional, Simpson, Philippa J.L., additional, Lam, Yuen Ting, additional, Jenkins, Alicia J., additional, Bursill, Christina A., additional, Keech, Anthony C., additional, and Ng, Martin K.C., additional

Published
2019
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13. High-density lipoproteins rescue diabetes-impaired angiogenesis via scavenger receptor class B type I

Author

Tan, Joanne T.M., Prosser, Hamish C.G., Dunn, Louise L., Vanags, Laura Z., Ridiandries, Anisyah, Tsatralis, Tania, Lecce, Laura, Clayton, Zoë E., Yuen, Sui Ching G., Robertson, Stacy, Lam, Yuen Ting, Celermajer, David S., Ng, Martin K.C., and Bursill, Christina A.

Abstract

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose–induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI−/− diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.

Published
2016

14. CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries

Author

Michelis, Katherine C., primary, Nomura-Kitabayashi, Aya, additional, Lecce, Laura, additional, Franzén, Oscar, additional, Koplev, Simon, additional, Xu, Yang, additional, Santini, Maria Paola, additional, D'Escamard, Valentina, additional, Lee, Jonathan T.L., additional, Fuster, Valentin, additional, Hajjar, Roger, additional, Reddy, Ramachandra C., additional, Chikwe, Joanna, additional, Stelzer, Paul, additional, Filsoufi, Farzan, additional, Stewart, Allan, additional, Anyanwu, Anelechi, additional, Björkegren, Johan L.M., additional, and Kovacic, Jason C., additional

Published
2018
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16. CD90 MARKS A POPULATION OF ADVENTITIAL MESENCHYMAL STEM CELLS IN THE HUMAN AORTA THAT EXHIBIT DIMINISHED ANGIOGENIC POTENTIAL IN PATIENTS WITH ASCENDING AORTIC ANEURYSMS

Author

Michelis, Katherine, primary, Kitabayashi, Aya, additional, Lecce, Laura, additional, Santini, Maria Paola, additional, D'Escamard, Valentina, additional, Franzén, Oscar, additional, Björkegren, Johan L.M., additional, Fuster, Valentin, additional, Reddy, Ramachandra, additional, Chikwe, Joanna, additional, Stelzer, Paul, additional, Filsoufi, Farzan, additional, Stewart, Allan, additional, Anyanwu, Ani, additional, and Kovacic, Jason, additional

Published
2017
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19. Fenofibrate Rescues Diabetes-Related Impairment of Ischemia-Mediated Angiogenesis by PPARα-Independent Modulation of Thioredoxin-Interacting Protein.

Author

King, Emily J., Lecce, Laura, Simpson, Philippa J. L., Jun Yuan, Yuen Ting Lam, Tan, Joanne T. M., Bursill, Christina A., Rajamani, Kushwin, Ng, Martin K. C., Jenkins, Alicia J., Keech, Anthony C., Solly, Emma L., Yuan, Jun, and Lam, Yuen Ting

Subjects
*THIOREDOXIN-interacting protein, *FENOFIBRATE, *VASCULAR endothelial growth factors, *LEG amputation, *PEROXISOME proliferator-activated receptors
Abstract

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduces lower limb amputations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose-impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate. [ABSTRACT FROM AUTHOR]

Published
2019
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20. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability

Author

Evrard, Solene M., primary, Lecce, Laura, additional, Michelis, Katherine C., additional, Nomura-Kitabayashi, Aya, additional, Pandey, Gaurav, additional, Purushothaman, K-Raman, additional, d’Escamard, Valentina, additional, Li, Jennifer R., additional, Hadri, Lahouaria, additional, Fujitani, Kenji, additional, Moreno, Pedro R., additional, Benard, Ludovic, additional, Rimmele, Pauline, additional, Cohain, Ariella, additional, Mecham, Brigham, additional, Randolph, Gwendalyn J., additional, Nabel, Elizabeth G., additional, Hajjar, Roger, additional, Fuster, Valentin, additional, Boehm, Manfred, additional, and Kovacic, Jason C., additional

Published
2016
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28. O022 Striking Differences In The Role of Distinct Endothelial Progenitor Cell Populations In Ischaemia-Mediated Neovascularisation And Coronary Collateral Formation - Implications On Therapeutic Angiogenesis

Author

Yuen, Sui Ching G., primary, Chan, Kim H., additional, Simpson, Philippa, additional, Clayton, Zoe, additional, Dantanarayana, Ashanti, additional, Lecce, Laura, additional, Dunn, Louise, additional, Yong, Andy, additional, Hsu, Chi-Jen, additional, Guillou, Matt, additional, Bao, Shisan, additional, Chawantanpipat, Chirapan, additional, Celermajer, David, additional, Wu, Joseph, additional, and Ng, Martin, additional

Published
2014
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37. Corrigendum: Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability.

Author

Evrard, Solene M., Lecce, Laura, Michelis, Katherine C., Nomura-Kitabayashi, Aya, Pandey, Gaurav, Purushothaman, K-Raman, d'Escamard, Valentina, Li, Jennifer R., Hadri, Lahouaria, Fujitani, Kenji, Moreno, Pedro R., Benard, Ludovic, Rimmele, Pauline, Cohain, Ariella, Mecham, Brigham, Randolph, Gwendalyn J., Nabel, Elizabeth G., Hajjar, Roger, Fuster, Valentin, and Boehm, Manfred

Published
2017
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38. High-Density Lipoproteins Rescue Diabetes-Impaired Angiogenesis via Scavenger Receptor Class B Type I.

Author

Tan JT, Prosser HC, Dunn LL, Vanags LZ, Ridiandries A, Tsatralis T, Lecce L, Clayton ZE, Yuen SC, Robertson S, Lam YT, Celermajer DS, Ng MK, and Bursill CA

Subjects
Animals, Blood Glucose drug effects, Cell Line, Cholesterol blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Diabetes Mellitus, Experimental, Disease Models, Animal, Humans, Immunohistochemistry, Lipoproteins, HDL blood, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, Nuclear Proteins metabolism, Regional Blood Flow drug effects, Regional Blood Flow genetics, Scavenger Receptors, Class B genetics, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Lipoproteins, HDL therapeutic use, Neovascularization, Physiologic drug effects, Scavenger Receptors, Class B metabolism, Wound Healing drug effects
Abstract

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose-induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI(-/-) diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications., (© 2016 by the American Diabetes Association.)

Published
2016
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