Treatment of calcific arterial disease via enhancement of autophagy using GSK343

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch. [Display omitted] •Impaired autophagy initiation is a determinant of vascular calcification•Chromatin rearrangement at autophagy genes in calcified VSMCS•Chromatin relaxation by GSK343 restores autophagy initiation gene expression•Pharmacologic or genetic enhancement of autophagy inhibits vascular calcification Cardiovascular medicine; Human Genetics; Molecular physiology