Haplo-insufficiency of Profilin1 in vascular endothelial cells is beneficial but not sufficient to confer protection against experimentally induced atherosclerosis

Abstract

AbstractActin cytoskeleton plays an important role in various aspects of atherosclerosis, a key driver of ischemic heart disease. Actin-binding protein Profilin1 (Pfn1) is overexpressed in atherosclerotic plaques in human disease, and Pfn1, when partially depleted globally in all cell types, confers atheroprotectionin vivo. This study investigates the impact of endothelial cell (EC)-specific partial loss of Pfn1 expression in atherosclerosis development. We utilized mice engineered for conditional heterozygous knockout of the Pfn1 gene in ECs with atherosclerosis induced by PCSK9-encoding adeno-associated virus-mediated depletion of hepatic LDL receptor combined with high-cholesterol diet. Our studies show that partial depletion of EC Pfn1 has certain beneficial effects marked by dampening of select pro-atherogenic cytokines (CXCL10 and IL7) with concomitant reduction in cytotoxic T cell abundance but is not sufficient to reduce hyperlipidemia and confer atheroprotectionin vivo. In light of these findings, we conclude that atheroprotective phenotype conferred by global Pfn1 haplo-insufficiency requires contributions of additional cell types that are relevant for atherosclerosis progression.