HELIOS

Despite decades of lipid lowering drug delivery, prevention strategies and efforts in research, cardiovascular diseases, mainly caused by atherosclerosis, are still the leading cause of death worldwide. New therapies are then mandatory to reduce the residual cardiovascular risk and to prevent atherothrombotic events. Atherosclerosis is a chronic inflammatory disease of the vascular wall triggered by low density lipoprotein internalisation within the subendothelial space. More than the obstruction of the arterial lumen, instability and rupture of the plaque are now recognized as the most deleterious events. Among processes triggering plaque instability, intraplaque neovascularization accelerates plaque progression, induces plaque rupture and attenuates statin benefit in human. Our preliminary data identified the nuclear receptor Rev-erb-a as a putative inhibitor of intraplaque neovascularization in human and mouse plaques in vivo as well as in vitro in endothelial cells. We then hypothesize that Rev-erb-a represents a new anti-atherogenic target that prevents intraplaque neovascularization by inhibiting the angiogenic activity of endothelial cells. This proposal will be the first to address the role of Rev-erba in angiogenesis and intraplaque neovascularization. This project will involve original available mouse models, innovative validated whole organ imaging techniques, in combination with cellular omics and mechanistic studies and a translational clinical part addressing the relevance of experimental results to human disease. We anticipate to identify Rev-erb-a as a novel therapeutic target to reduce intraplaque neovascularization and cardiovascular diseases.