Novel treatment of small and large artery calcific disease via epigenetic activation of autophagy initiation genes

Abstract Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events1. Growing evidence points towards macroautophagy (herein referred to simply as autophagy), a cellular self-degradation process, as being protective during early atherosclerosis2. However, autophagy may become dysregulated with advanced atherosclerosis3. Vascular smooth muscle cells (VSMC) contribute to early and advanced atherosclerosis by regulating vascular remodeling and calcification. The precise effects of autophagy on VSMC-mediated calcification are unknown. Here, we combined multi-omic profiling and high-resolution structural imaging to pinpoint an epigenetic mechanism by which impaired autophagy drives VSMC calcification. Our studies revealed dysfunctional autophagy initiation4 to be responsible for altered autophagy flux during VSMC calcification. In vivo pharmacologic and genetic activation of autophagy using chromatin modulator GSK343 and Becn1F121A knock-in mice, respectively, inhibited vascular calcification and improved survival rates in mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data enhance our mechanistic understanding of vascular calcification by specifically implicating impairment in the initiation of the autophagy pathway and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.