Molecular mechanisms and novel therapeutic approaches for cardiovascular calcification

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In this research project, we have gained several findings as described below.(1) We have established in vitro model of vascular calcification using human aortic smooth muscle cells (HASMC). In this model, we have observed that phosphate-induced SMC calcification involves osteoblast-like transformation via Na-dependent Pi cotransporter activation. Furthermore, we have got the results showing that phosphate induced SMC calcification as well as apoptosis in a concentration-dependent manner and the inhibition of apoptosis by the caspase inhibitor prevented SMC calcification, suggesting the essential role of SMC apoptosis in calcification. We have also identified the downregulation of Gas6 and its receptor Axl as a cause of phosphate-induced SMC apoptosis and calcification.(2) We examined the effects of statins on SMC calcification. Statins prevented both SMC apoptosis as well as calcification. In addition, the inhibitory effects of statins were mainly mediated by the restoration of the downregulation of Gas6 and Axl induced by phosphate.(3) We have also established in vivo rat model of vascular calcification and confirmed the beneficial effects of statins, observed in in vitro model. Statins markedly suppressed aortic calcification in rat model of renal failure induced by adenine supplementation.(4) To identify the correlates with vascular calcification in patients, we evaluated the length of abdominal aortas in XP of 42 elderly patients and investigated the correlations with several variables. As a result, we found the positive correlation between length of aortic calcification and pulse pressure (r=0.54,p<0.01), suggesting aortic calcification as a structural substrate of aortic stiffness.