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

血管衰老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，因为异位钙化的硬化血管导致血压变异性过高，单纯的收缩期高血压伴动脉波反射增加，以及随后的脑/心血管(CV)事件。血管钙化以前被证明是由于衰老和骨质疏松导致的被动钙沉淀。然而，最近积累的证据表明，它可归因于一种类似于骨中成骨的主动“细胞介导过程”，而不是血管平滑肌细胞(SMC)中被动的矿物质沉积。细胞衰老最近被证明与动脉粥样硬化形成有关，然而，很少有报道指出细胞衰老是否与SMC钙化有关。我们的新发现表明，SMC的衰老表型改变与成骨细胞的转分化有关，哺乳动物sirtuin SIRT1是一个众所周知的长寿基因，它对高磷血症下细胞衰老相关的血管钙化具有保护作用。此外，SMC中的成骨转录因子Runx2的激活受SIRT1-p21轴的调控。寻找能够延缓甚至逆转SMC衰老表型改变的治疗靶点，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.