ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response
ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response
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ACE2和Ang-(1-7)通过抑制炎症反应保护内皮细胞功能并预防早期动脉粥样硬化
DOI：
10.1007/s00011-015-0805-1
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发表时间：
2015-04-01
影响因子：
6.7
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
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作者：
Zhang, Yue-Hui;Zhang, Yong-huan;Zhang, Yun
血管紧张素转换酶2（ACE2）是一种通过将血管紧张素II（Ang - II）转化为血管紧张素 -（1 - 7）[Ang -（1 - 7）]来对抗ACE的反向调节因子，但ACE2和Ang -（1 - 7）对内皮细胞功能和动脉粥样硬化进展的影响尚不清楚。我们假设ACE2过表达和Ang -（1 - 7）可能通过反向调节血管紧张素II信号传导和抑制炎症反应来保护内皮细胞功能。我们使用重组腺病毒载体在体外人内皮细胞和体内载脂蛋白E缺陷（apoE - deficient）小鼠中局部过表达ACE2基因（Ad - ACE2）。在体外评估了血管紧张素II诱导的单核细胞趋化蛋白 - 1（MCP - 1）、血管细胞黏附分子 - 1（VCAM - 1）和E - 选择素表达、内皮细胞迁移以及人单核细胞（U - 937）对人脐静脉内皮细胞（HUVECs）的黏附情况（通过ACE2基因转移）。在体内研究了加速的动脉粥样硬化情况，在载脂蛋白E缺陷小鼠中诱导动脉粥样硬化，并将其随机分为四组，分别接受ACE2基因转移（Ad - ACE2）、对照病毒（Ad - EGFP）、Ad - ACE2 + A779（一种Ang -（1 - 7）受体拮抗剂）以及对照组。基因转移4周后，评估动脉粥样硬化病理情况。ACE2基因转移不仅在体外促进了人脐静脉内皮细胞迁移，抑制了单核细胞对人脐静脉内皮细胞的黏附，并降低了血管紧张素II诱导的单核细胞趋化蛋白 - 1、血管细胞黏附分子 - 1和E - 选择素蛋白的产生，而且在体内降低了单核细胞趋化蛋白 - 1、血管细胞黏附分子 - 1和白细胞介素6的水平，并抑制了动脉粥样硬化斑块的进展。此外，给予A779在体内提高了单核细胞趋化蛋白 - 1、血管细胞黏附分子 - 1和白细胞介素6的水平，并导致动脉粥样硬化程度进一步加重。ACE2和Ang -（1 - 7）通过保护内皮功能和抑制炎症反应显著抑制早期动脉粥样硬化病变的形成。
Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1-7), but the effect of ACE2 and Ang-(1-7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1-7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response.We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E-selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1-7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated.ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent.ACE2 and Ang-(1-7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response.