Establishment of mouse model and treatment for vascular aging

血管细胞在体外培养时寿命有限，最终进入一种不可逆转的生长停滞状态，称为“细胞衰老”。我们发现在人类动脉粥样硬化性病变中存在衰老的血管细胞，但在非动脉粥样硬化性病变中没有。此外，这些细胞表达的促炎分子水平增加，内皮型一氧化氮合酶水平降低，提示体内细胞衰老参与了人类动脉粥样硬化和血管老化的发病机制。关于衰老的一个广泛讨论的假说是端粒假说。我们展示了端粒功能在调节血管功能和血管细胞寿命方面的关键作用。我们还发现，RAS的结构性激活过早地诱导了与血管炎症相关的血管细胞衰老。与对照损伤的动脉…相比，球囊损伤动脉中引入RAS可增强血管炎症和衰老更多的ES。此外，在人类动脉粥样硬化斑块中，衰老细胞表达炎症分子，并且ERK在这些细胞中被激活，这表明端粒非依赖性机制可能也有助于人类动脉粥样硬化中血管细胞的衰老。血管紧张素II(Ang II)是RAS的一种强有力的激活剂，据报道与多种人类血管疾病的发病有关。我们发现Ang II在体外和体内都通过诱导细胞衰老来促进血管炎症。抑制衰老可有效预防血管紧张素Ⅱ诱导的血管炎症。胰岛素/Akt途径成分的功能减退突变已被证明可以延长从酵母到小鼠的各种生物体的寿命。我们发现Akt活性随细胞衰老而增加，抑制Akt可延长原代培养的人内皮细胞的寿命。Akt的结构性激活通过依赖于p53/p21的途径促进细胞衰老样生长停滞，导致内皮功能障碍。Akt在调节细胞寿命方面的这一新作用可能与包括动脉粥样硬化和糖尿病在内的多种人类疾病有关。较少

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." We demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not non-atherosclerotic lesions. Moreover, these cells expressed increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis and vascular aging. One widely discussed hypothesis of senescence is the telomere hypothesis. We showed a critical role of telomere function in regulating vascular function as well as lifespan of vascular cells. We also found that constitutive activation of Ras prematurely induced vascular cell senescence that is associated with vascular inflammation. Introduction of Ras into balloon-injured arteries enhanced vascular inflammation as well as senescence compared with control-injured arteri … More es. Moreover, senescent cells express inflammatory molecules in human atherosclerotic plaque, and ERK is activated in these cells, suggesting that telomere-independent mechanisms may also contribute to vascular cell senescence in human atherosclerosis. Angiotensin II (Ang II) is a potent activator for Ras and has been reported to contribute to the pathogenesis of various human vascular diseases. We found that Ang II promoted vascular inflammation by inducing cellular senescenee both in vitro and in vivo. Inhibition of senescence effectively prevented Ang II-induced vascular inflammation. Reduction-of-function mutations in components of the insulin/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. We showed here that Akt activity increased with cellular senescence and that inhibition of Akt extended the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promoted senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human, diseases including atherosclerosis and diabetes mellitus. Less