Histone deacetylase 9 promotes endothelial to mesenchymal transition and an unfavorable atherosclerotic plaque phenotype

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

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial to 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. In particular, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype
remain unclear. Here we identified histone deacetylation, specifically HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, class IIa HDAC inhibition was found to sustain the expression of endothelial proteins and mitigate 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 between EndMT, HDAC9, and atherosclerosis, and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or to slow the progression of atherosclerotic disease.
Original languageEnglish
JournalJournal of Clinical Investigation
DOIs
Publication statusPublished - 2 Aug 2021

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