Angiotensin-Converting Enzyme 2 Is a Critical Determinant of Angiotensin II-Induced Loss of Vascular Smooth Muscle Cells and Adverse Vascular Remodeling
Angiotensin-Converting Enzyme 2 Is a Critical Determinant of Angiotensin II-Induced Loss of Vascular Smooth Muscle Cells and Adverse Vascular Remodeling
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血管紧张素转换酶 2 是血管紧张素 II 诱导的血管平滑肌细胞损失和不良血管重塑的关键决定因素
DOI：
10.1161/hypertensionaha.114.03388
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发表时间：
2014-07-01
期刊：
影响因子：
8.3
通讯作者：
Oudit, Gavin Y.
中科院分区：
文献类型：
--
作者：
Patel, Vaibhav B.;Zhong, Jiu-Chang;Oudit, Gavin Y.
血管紧张素转换酶（ACE）2是肾素-血管紧张素系统的关键负调节因子，将血管紧张素II（Ang II）代谢为Ang 1至7。Ang II是一种血管活性肽，在血管疾病中发挥重要作用。本研究的目的是明确 ACE2 在病理性血管重塑中的作用。我们发现，在具有二叶式主动脉瓣的扩张的人主动脉中以及在小鼠主动脉中，ACE2 因 Ang II 的反应而上调。离体压力肌动描记显示，ACE2 敲除 (KO) 肠系膜动脉的血管僵硬度随着 Ang II（每天 1.5 毫克/千克）和衰老的反应而增加。组织学分析显示，ACE2KO 肠系膜动脉中管腔比降低，血管平滑肌细胞丢失。 ACE2KO 小鼠的主动脉血管平滑肌细胞对 Ang II 的反应显示出活性氧和细胞凋亡显着增加，同时 ACE2KO 主动脉中 cleaved caspase-3 和 cleaved caspase-8 水平增加。 Ang II 1 型受体阻断和 Ang 1 至 7 补充可防止 Ang II 诱导的活性氧增加和细胞凋亡。在主动脉中，Ang II 导致胸主动脉和腹主动脉扩张，并伴有 ACE2KO 主动脉中血管平滑肌细胞密度的损失，如 β-平滑肌肌动蛋白、钙调蛋白染色和电子显微镜检查显示的前基质金属蛋白酶 2、基质金属蛋白酶 2 和基质金属蛋白酶 9 水平增加。 ACE2 在血管疾病中表达上调，ACE2 缺乏会加剧由活性氧增加和血管平滑肌细胞凋亡驱动的 Ang II 介导的血管重塑。总之，ACE2 针对激活的肾素-血管紧张素系统的关键反调节作用为 ACE2 在血管疾病中的作用提供了新的见解。
Angiotensin-converting enzyme (ACE) 2 is a key negative regulator of the renin-angiotensin system and metabolizes angiotensin II (Ang II) into Ang 1 to 7. Ang II is a vasoactive peptide, which plays an important role in vascular disease. The objective of the present study was to define the role of ACE2 in pathological vascular remodeling. We found upregulation of ACE2 in dilated human aorta with bicuspid aortic valve and in murine aorta in response to Ang II. Ex vivo pressure myography showed increased vascular stiffness in ACE2 knockout (KO) mesenteric arteries in response to Ang II (1.5 mg/kg per day) and with aging. Histological analyses revealed reduced media-to-lumen ratio in ACE2KO mesenteric arteries with loss of vascular smooth muscle cells. Aortic vascular smooth muscle cells from ACE2KO mice showed markedly increased reactive oxygen species and apoptosis in response to Ang II along with increased cleaved caspase-3 and cleaved caspase-8 levels in the ACE2KO aorta. Ang II type 1 receptor blockade and Ang 1 to 7 supplementation prevented the increase in Ang II-induced reactive oxygen species and apoptotic cell death. In the aorta, Ang II resulted in thoracic and abdominal aortic dilation with loss of vascular smooth muscle cell density in ACE2KO aorta as revealed by -smooth muscle actin, calponin staining, and electron microscopy with increased promatrix metalloproteinase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 levels. ACE2 is upregulated in vascular diseases, and ACE2 deficiency exacerbates Ang II-mediated vascular remodeling driven by increased reactive oxygen species and vascular smooth muscle cell apoptosis. In conclusion, the key counter-regulatory role of ACE2 against an activated renin-angiotensin system provides novel insights into the role of ACE2 in vascular diseases.