Oudit Gavin Y, Kassiri Zamaneh, Patel Mikin P, Chappell Mark, Butany Jagdish, Backx Peter H, Tsushima Robert G, Scholey James W, Khokha Rama, Penninger Josef M
Division of Cardiology, Department of Medicine, University of Toronto, Canada.
Cardiovasc Res. 2007 Jul 1;75(1):29-39. doi: 10.1016/j.cardiores.2007.04.007. Epub 2007 Apr 21.
The peptidase action of angiotensin converting enzyme 2 (ACE2) allows it to function as a negative regulator of the renin-angiotensin system. Current pharmacotherapies for human heart failure, such as ACE inhibitors and angiotensin and aldosterone receptor blockers, increase the activity of ACE2 in the heart. In this study, we investigate the mechanism for the age-dependent cardiomyopathy in ACE2 null mice.
Ace2(-/y) mutant mice develop a progressive age-dependent dilated cardiomyopathy with increased oxidative stress, neutrophilic infiltration, inflammatory cytokine and collagenase levels, mitogen-activated protein kinase (MAPK) activation and pathological hypertrophy. The angiotensin II receptor-1 (AT1) blocker, irbesartan, prevented the dilated cardiomyopathy in aged Ace2(-/y) mutant mice, confirming a critical role of angiotensin II (Ang II)-mediated stimulation of AT1 receptors. Ang II activation of AT1 receptors triggers G-protein-coupled receptor (GPCR)-activated phosphoinositide 3-kinase gamma (PI3Kgamma) and its downstream pathways. We showed that p110gamma, the catalytic subunit of PI3Kgamma, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2(-/y)/p110gamma(-/-)) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3Kgamma plays a critical role in Ang II-mediated cardiomyopathy.
Our findings demonstrate that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors. Our combination of genetic and pharmacological approaches defines a critical role of ACE2 in the suppression of Ang II-mediated heart failure.
血管紧张素转换酶2（ACE2）的肽酶作用使其能够作为肾素-血管紧张素系统的负调节因子发挥作用。目前用于治疗人类心力衰竭的药物疗法，如ACE抑制剂以及血管紧张素和醛固酮受体阻滞剂，会增加心脏中ACE2的活性。在本研究中，我们探究了ACE2基因敲除小鼠中年龄依赖性心肌病的发病机制。
Ace2（- / y）突变小鼠会发生进行性年龄依赖性扩张型心肌病，伴有氧化应激增加、中性粒细胞浸润、炎性细胞因子和胶原酶水平升高、丝裂原活化蛋白激酶（MAPK）激活以及病理性肥大。血管紧张素II受体-1（AT1）阻滞剂厄贝沙坦可预防老年Ace2（- / y）突变小鼠发生扩张型心肌病，证实了血管紧张素II（Ang II）介导的AT1受体刺激起关键作用。Ang II激活AT1受体可触发G蛋白偶联受体（GPCR）激活的磷酸肌醇3激酶γ（PI3Kγ）及其下游通路。我们发现，PI3Kγ的催化亚基p110γ是Ang II刺激下NADPH氧化酶激活的关键介质。双突变小鼠（Ace2（- / y）/ p110γ（- / -））的氧化应激、中性粒细胞浸润和病理性肥大显著减轻，从而实现心肌保护，这表明PI3Kγ在Ang II介导的心肌病中起关键作用。
我们的研究结果表明，ACE2基因敲除小鼠中的年龄依赖性心肌病与通过AT1受体增加的Ang II介导的氧化应激和中性粒细胞浸润有关。我们采用的基因和药理学方法相结合的研究确定了ACE2在抑制Ang II介导的心力衰竭中的关键作用。
