Journal Article

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

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

2021

Overview

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 IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa 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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Atherosclerosis - enzymology / Atherosclerosis - genetics / Atherosclerosis - pathology / Atherosclerotic plaque / Cardiovascular research / Cell differentiation / Development and progression / Endothelium - enzymology / Endothelium - pathology / Epithelial cells / Genetic aspects / Health aspects / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Human Umbilical Vein Endothelial Cells / Humans / Mice / Mice, Knockout, ApoE / Phenotype / Plaque, Atherosclerotic - enzymology / Plaque, Atherosclerotic - genetics / Plaque, Atherosclerotic - pathology / Repressor Proteins - genetics / Repressor Proteins - metabolism / Stem cells