Pivotal role of longevity gene Sir2 on molecula r mechanisms of vascular calcification via cellular senescence

血管老化表现为动脉粥样硬化、硬化和钙化改变。血管钙化使老年人的血流动力学管理更加困难，因为异位钙化导致血管硬化，导致血压变异性过大，孤立性收缩期高血压伴动脉波反射增加，以及随后的缺血性脑/心血管（CV）事件。血管钙化以前已被证明是由于钙的被动沉淀与衰老和骨质疏松症。然而，最近越来越多的证据表明，这是由于一个积极的“细胞介导的过程”类似骨的骨生成，而不是被动的血管平滑肌细胞（SMC）中的矿物质沉淀。细胞衰老最近已被证明与动脉粥样硬化发生，然而，很少有报告指出细胞衰老是否与SMC钙化。我们的新发现表明，衰老表型变化与SMC中的成骨细胞转分化有关，哺乳动物sirtuin SIRT 1是一种众所周知的长寿基因，可以对高磷血症下细胞衰老相关的血管钙化发挥保护作用。此外，SMC中的Runx 2（一种有效的成骨转录因子）的激活受SIRT 1-p21轴的调节。确定治疗靶点，可以减缓进展，甚至逆转SMC的衰老表型变化可能是血管钙化治疗的重要一步。

Vascular aging manifest several features, namely atherosis, sclerosis and calcified change. Vascular calcification makes the management of hemodynamics more difficult in the elderly, because the stiffened vasculatures with ectopic calcification contribute to excessive blood pressure variability, isolated systolic hypertension with increased arterial wave reflectance, and subsequent ischemic cerebro-/cardio-vascular(CV) events. Vascular calcification has been previously shown to result from passive precipitation of calcium with aging and osteoporosis. However, accumulating recent evidences have shown it to be attributable to an active' cell-mediated process' resembling osteogenesis in bone rather than passive mineral precipitation in vascular smooth muscle cells(SMC). Cellular senescence has been recently shown to be linked to atherosclerogenesis ; however, few reports have addressed whether cellular senescence is associated with SMC calcification. Our new findings show that the senescent phenotypic change is associated with osteoblastic trans-differentiation in SMC and mammalian sirtuin SIRT1, which is well known as a longevity gene, can exert a protective effect on the cellular senescence-related vascular calcification under hyperphosphatemia. In addition, the activation of Runx2, a potent osteogenic transcriptional factor, in SMC is regulated by SIRT1-p21 axis. The identification of therapeutic targets which can slow down the progression or even reverse the senescent phenotypic change in SMC could be an important step forward in the treatment of vascular calcification.