Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway
Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway
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血管紧张素-(1-9) 通过 CNPY2/PERK 通路预防血管紧张素 II 诱导的内皮细胞凋亡
DOI：
10.1007/s10495-022-01793-2
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发表时间：
2022-11-22
期刊：
影响因子：
7.2
通讯作者：
Lu, Zhao-yang
中科院分区：
文献类型：
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作者：
Guo, Chun-ling;Liu, Hui-min;Lu, Zhao-yang
血管紧张素系统（RAS）激活引起的内皮细胞凋亡在高血压的发生、发展中起重要作用。血管紧张素-（1-9）（Angiotensin-（1 - 9），Ang-（1-9））是血管内皮细胞（vascular endothelial cells，ECs）中一种具有抗高血压作用的非经典RAS肽。然而，其作用机制仍不清楚。认为内皮细胞凋亡与内质网应激和线粒体功能密切相关。本研究旨在探讨血管紧张素-（1-9）在血管紧张素II（Ang II）诱导的高血压中对内皮细胞凋亡的影响及其分子机制。在人脐静脉内皮细胞（HUVECs）中，我们观察到Ang-（1-9）抑制Ang II诱导的ERS相关的内皮细胞凋亡。Ang-（1-9）通过阻断CNPY 2/PERK介导的CaMKII/Drp 1依赖的线粒体分裂和eIF 2 α/CHOP信号抑制内皮细胞凋亡。与上述HUVECs的作用一致，在Ang II诱导的高血压小鼠中，我们发现给予外源性Ang-（1-9）可减轻内皮细胞凋亡和动脉血压，这是通过CNPY 2/PERK信号通路介导的。我们的研究表明Ang-（1-9）通过CNPY 2/PERK通路抑制Ang II诱导的高血压。这些发现可能为今后高血压的预防和治疗提供新的见解。
Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2 alpha/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.