State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beilishi Road 167, Xicheng District, Beijing 100037, China.
State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beilishi Road 167, Xicheng District, Beijing 100037, China.
Exp Gerontol. 2019 May;119:212-220. doi: 10.1016/j.exger.2019.02.012. Epub 2019 Feb 16.
The role of angiotensin II (Ang II) in hypertension has been clarified, but recent studies show that aging-associated arterial changes and those with hypertension as well as atherosclerosis may have some common pathogenesis. This study aimed to clarify the effects of Ang II on endothelial senescence by establishing a replicative senescence model of human umbilical vein endothelial cells (HUVECs) in vitro. The population-doubling level (PDL) was calculated, PDL5 and PDL25 respectively referred to cells cultured for 2 days and 30 days. Compared with Ang II-treated young PDL5 cells, chronic stimulation of Ang II significantly promoted the senescence-associated β-galactosidase activity and expression of senescence-related genes p16 and p21, slowed down cell growth rate, and decreased expression of longevity-related genes sirtuin1 as well as telomerase activity in senescent PDL25 cells (all P < 0.05). Moreover, expression of pro-inflammatory cytokines and adhesion molecules were up-regulated in Ang II-treated PDL25 cells (all P < 0.05). Ang II-induced senescent progression and inflammation were attenuated by angiotensin receptor blocker valsartan. In young PDL5 cells, Ang II promoted the endothelial viability including cell proliferation, migration, angiogenesis and cell adhesion to monocytes; however, chronic stimulation of Ang II suppressed the cell viability, promoted cell adhesion and apoptosis in senescent PDL25 cells, which could be ameliorated by short-term valsartan, but long-term valsartan had no effects. In addition, Ang II-induced senescent features could be partly recovered if Ang II was stopped at PDL20. These findings suggested that chronic stimulation of Ang II can accelerate the endothelial senescence process which is implicated in aging-related atherosclerosis.
血管紧张素 II（Ang II）在高血压中的作用已经阐明，但最近的研究表明，与衰老相关的动脉变化以及高血压和动脉粥样硬化可能具有一些共同的发病机制。本研究旨在通过建立人脐静脉内皮细胞（HUVEC）体外复制衰老模型，阐明 Ang II 对内皮细胞衰老的影响。计算群体倍增水平（PDL），PDL5 和 PDL25 分别表示培养 2 天和 30 天的细胞。与 Ang II 处理的年轻 PDL5 细胞相比，慢性 Ang II 刺激显著促进衰老相关β-半乳糖苷酶活性和衰老相关基因 p16 和 p21 的表达，减缓细胞生长速度，并降低长寿相关基因 sirtuin1 的表达以及衰老 PDL25 细胞中的端粒酶活性（均 P<0.05）。此外，Ang II 处理的 PDL25 细胞中促炎细胞因子和黏附分子的表达上调（均 P<0.05）。血管紧张素受体阻滞剂缬沙坦可减轻 Ang II 诱导的衰老进展和炎症。在年轻的 PDL5 细胞中，Ang II 促进了内皮细胞的活力，包括细胞增殖、迁移、血管生成和细胞与单核细胞的黏附；然而，慢性 Ang II 刺激抑制了衰老 PDL25 细胞的细胞活力，促进了细胞黏附和凋亡，短期缬沙坦可改善这种情况，但长期缬沙坦则没有效果。此外，如果在 PDL20 时停止 Ang II，Ang II 诱导的衰老特征可以部分恢复。这些发现表明，慢性 Ang II 刺激可加速与衰老相关的动脉粥样硬化有关的内皮细胞衰老过程。
