Mario Negri Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy.
Pflugers Arch. 2010 Jan;459(2):325-32. doi: 10.1007/s00424-009-0725-4. Epub 2009 Sep 11.
Angiotensin II (Ang II), the central product of renin-angiotensin system, has a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT(1)). Several experimental studies have demonstrated that Ang II acts through AT(1) as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT(1A)) in mice translates into marked prolongation of life span. The absence of AT(1A) protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT(1) receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT(1) pathway represents a feasible therapeutic strategy to prolong life span in humans.
血管紧张素 II（Ang II）是肾素-血管紧张素系统的中心产物，在人类高血压的病因学和心脏及肾脏疾病的病理生理学中起作用。Ang II 的其他功能包括对免疫反应、炎症、细胞生长和增殖的影响，这些功能主要通过 Ang II 型 1 受体（AT（1））介导。几项实验研究表明，Ang II 通过 AT（1）作为正常衰老过程的中介物发挥作用，通过增加线粒体的氧化损伤，从而影响线粒体功能。最近，我们小组证明，通过靶向敲除编码 Ang II 型 1A 受体（AT（1A））的 Agtr1a 基因抑制 Ang II 活性，可显著延长小鼠的寿命。缺乏 AT（1A）可保护多个器官免受氧化损伤，减轻与衰老相关的表型与增加的线粒体数量和生存相关基因 Sirtuin 3 的上调有关。AT（1）受体拮抗剂已被证明可安全耐受慢性使用，并被用作高血压和心力衰竭现代治疗的关键组成部分，因此 Ang II/AT（1）途径代表了延长人类寿命的可行治疗策略。
