Abstract 330: Autophagy in Vascular Calcification

Vascular calcification accompanies a variety of common cardiovascular-related diseases and correlates with premature death. Vascular calcification is a highly-regulated process but the precise mechanisms inducing this pathology are not fully understood, and currently no treatment exists that halts or reverses vascular calcification. We previously discovered the rare monogenetic disease Arterial Calcification due to Deficiency of CD73 (ACDC) which presents with vessel tortuosity and extensive calcifications in the medial layer of lower-extremity arteries. To study the mechanisms underlying this disease we previously created ACDC and Control patient iPSCs, and using a teratoma assay discovered that ACDC iPSC teratomas exhibit extensive calcifications, while Control iPSC teratomas do not. Drug screening identified that rapamycin inhibited calcification in this in vivo model. Using our in vitro calcification model with ACDC fibroblasts, we again found that rapamycin inhibited calcification, as well as expression and activity of the key enzyme involved in ectopic calcification, tissue non-specific alkaline phosphatase (TNAP). To corroborate these findings in vascular cells we used coronary artery smooth muscle cells (CASMCs) in our in vitro calcification assay. We found CASMCs calcify in vitro, and that both rapamycin treatment, and importantly, specific activation of autophagy, inhibited calcification in CASMCs. This suggests autophagy as a therapeutic target for the treatment of vascular calcification. Future work will identify how autophagy prevents calcification, and whether rapamycin, which induces autophagy, can be used as a therapy for medial calcification.