Rev-erb-alpha inhibits vascular calcification by repressing osteogenic reprogramming in atherosclerosis
Year: 2026
Type: preprint
Abstract: Background Atherosclerotic plaque rupture is the leading cause of fatal atherothrombotic events, including myocardial infarction. Intimal microcalcification is a major determinant of plaque instability, but its pathogenic mechanisms remain poorly understood. The nuclear receptor Rev-erb-alpha regulates lipoprotein metabolism and inflammation. We hypothesized that it modulates atherogenesis by also controlling arterial calcification. Methods To identify regulators of vascular calcification, transcriptomic analysis of CD14+CD16- monocytes from diabetic patients with different calcium scores (ANGIOSAFE cohort) was combined with targeted analysis in calcified and non-calcified atherosclerotic plaques from diabetic and non-diabetic patients (AtheroPortal cohort) and in calcified and non-calcified areas of human endarterectomies isolated by laser capture microdissection (OPAL Cohort). Functional relevance was evaluated in 18-month-old Ldlr-/- mouse and in primary aortic vascular smooth muscle cells after targeting Rev-erb-alpha. Results In ANGIOSAFE (n=668), REV-ERB-alpha expression was lower in classical CD14+CD16- monocytes from diabetic patients with low coronary artery calcium scores. In the AtheroPortal cohort (n=968), REV-ERB-alpha expression was reduced in highly calcified plaques from diabetic patients, and laser capture microdissection confirmed lower expression in calcified compared to non-calcified areas of human endarterectomies. Rev-erb alpha-deficient Ldlr-/- mice displayed accelerated atherogenesis and calcification, with SMCs reprogrammed toward an osteochondroblastic phenotype. In vitro, Rev-erb-alpha preserved SMC identity by repressing IL-1-beta-driven transdifferentiation, notably via Spp1, Osterix and Sox9, and repressed the hyaluronidase Cemip, whose activity degrades hyaluronic acid and promotes intimal calcification. Conclusions Rev-erb-alpha restrains SMC-driven vascular calcification by suppressing osteogenic reprogramming, and may represent a therapeutic target to reduce calcification and cardiovascular risk in high-risk patients.
Authors: Lise Ferri, Cecilia Bellengier, Marc Diedisheim, antonino bongiovanni, Jean-Baptiste Julla, Stephane Delhaye, Ghania Kara-Ali, Christian Duhem, Salome Farge, Quentin Thorel, Aurore Hebras, Margaux Leduc, Sandrine Quemener, Delphine Eberle, David Dombrowicz, Annabelle Dupont, Mickael Rosa, Stephane Germain, Yasmine Sebti, Meryem Tardivel, Nicolas Venteclef, Joel T Haas, Bart Staels, Jean-François Gautier, Helene Duez, Benoit Pourcet
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223015822