Loss of TDAG51 attenuates aorta smooth muscle to osteoblast trans‐differentiation and calcification

Vascular calcification increases the mortality and morbidity associated with end stage renal disease (ESRD) by pre‐disposing blood vessels to rupture leading to heart attack and stroke. Hyperphosphotemia is a critical initiator of vascular calcification. Based on the observation that blood vessels from T‐cell death associated gene 51 (TDAG51) knock‐out mice show reduced Ca2+ deposition, we hypothesize that TDAG51 is a novel mediator of vascular calcification. Results indicate that TDAG51 is up‐regulated at the mRNA and protein level in human aortic smooth muscle cells (ASMC) and mouse ASMC exposed to high phosphate. High phosphate treated TDAG51−/− MASMC have significantly less cellular Ca2+ deposition/mg protein, reduced mineralization observed via von Kossa and xylenol orange staining and decreased alkaline phosphatase activity. Moreover, peroxisome proliferator‐activated receptor gamma mRNA and protein levels are up‐regulated in TDAG51−/− MASMC, whereas osteoblast differentiation marker RUNX2/Cbfa1 is down‐regulated. Interestingly, TDAG51−/− MASMC α‐actin is not well organized into contractile filaments. Thus, the loss of TDAG51 may confer resistance to vascular calcification and smooth muscle to osteoblast trans‐differentiation, thereby decreasing the risk of cardiovascular disease in ESRD. Supported by CIHR MOP‐67116.