Molecular mechanisms and novel therapeutic approaches for cardiovascular calcification

在本研究项目中，我们取得了如下研究成果：(1)利用人主动脉平滑肌细胞(HASMC)建立了体外血管钙化模型。在这个模型中，我们观察到磷酸盐诱导的SMC钙化涉及到通过钠依赖的PI辅助转运体激活的成骨细胞样转化。此外，我们还发现，磷酸盐以浓度依赖的方式诱导SMC钙化和凋亡，而caspase抑制剂抑制凋亡阻止了SMC钙化，提示SMC凋亡在钙化过程中起着重要作用。我们还发现Gas6及其受体Axl的下调是磷酸盐诱导的SMC凋亡和钙化的原因。(2)我们检测了他汀类药物对SMC钙化的影响。他汀类药物既能阻止SMC的凋亡，也能阻止钙化。此外，他汀类药物的抑制作用主要是通过恢复磷酸盐诱导的Gas6和Ax1的下调来实现的。(3)我们还建立了体内大鼠血管钙化模型，证实了他汀类药物的有益作用，体外观察到了他汀类药物的作用。他汀类药物明显抑制腺嘌呤肾衰大鼠模型的腹主动脉钙化。(4)为了确定与患者血管钙化的相关性，我们对42例老年患者的腹主动脉长度进行了测量，并研究了几个变量之间的相关性。结果发现，主动脉钙化长度与脉压呈正相关(r=0.54，p&lt；0.01)，提示主动脉钙化是主动脉僵硬的结构性底物。

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.