Mechanical Stretch Induces Smooth Muscle Cell Dysfunction by Regulating ACE2 via P38/ATF3 and Post-transcriptional Regulation by miR-421.
Mechanical Stretch Induces Smooth Muscle Cell Dysfunction by Regulating ACE2 via P38/ATF3 and Post-transcriptional Regulation by miR-421.
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机械拉伸通过 P38/ATF3 调节 ACE2 和 miR-421 转录后调节诱导平滑肌细胞功能障碍
DOI：
10.3389/fphys.2020.540591
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发表时间：
2020
影响因子：
4
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Liu X;Liu X;Li M;Zhang Y;Chen W;Zhang M;Zhang C;Zhang M
机械牵张促进高血压诱导的血管重构过程中血管平滑肌细胞（VSMC）功能失调。ACE 2具有广泛的心血管和肾脏保护作用。ACE 2的缺失与心血管疾病有关，但对其表达的调控知之甚少，特别是高血压期间异常机械牵张。本研究旨在探讨ACE 2在机械牵张条件下血管重构中的作用及其可能的机制。建立腹主动脉缩窄模型，模拟体内环境。FX-5000 T应变单元提供体外机械拉伸。采用过表达分析ACE 2在VSMCs增殖、迁移、凋亡及胶原代谢中的作用。采用RT-qPCR、Western blot、荧光素酶和ChIP等方法研究牵张对ACE 2表达的影响。我们发现机械牵张可调节ACE 2/Ang-（1-7）和ACE/AngII轴的表达。ACE 2对牵张敏感，参与牵张诱导的血管平滑肌细胞功能障碍。p38 MAPK/ATF 3通路和miR-421参与了ACE 2的调控。因此，ACE 2可能有助于机械牵张条件下血管重塑的发展。机械牵张可能通过p38 MAPK/ATF 3途径降低保护因子ACE 2的水平，促进ATF 3易位到细胞核中，ATF 3可通过miR-421的转录后调节直接与ACE 2启动子结合。
Mechanical stretch promotes deregulation of vascular smooth muscle cell (VSMC) functions during hypertension-induced vascular remodeling. ACE2 has a wide range of cardiovascular and renal protective effects. Loss of ACE2 is associated with cardiovascular disease, but little is known about the regulation of its expression, especially by abnormal mechanical stretch during hypertension. The present study was designed to investigate the contribution of ACE2 to vascular remodeling under mechanical stretch and to assess the possible underlying mechanisms. The abdominal aortic constriction model was established to mimic the environment in vivo. FX-5000T Strain Unit provided mechanical stretch in vitro. Overexpression was used to analyze the role of ACE2 played in the proliferation, migration, apoptosis, and collagen metabolism of the VSMCs. RT-qPCR, Western blot, luciferase assay, and ChIP assay were used to elucidate the molecular mechanism of ACE2 expression regulated by stretch. We found that mechanical stretch modulated the expression of the ACE2/Ang-(1–7) and ACE/AngII axis. ACE2 was mechanically sensitive and was involved in the stretch-induced dysfunction of VSMCs. The p38 MAPK/ATF3 pathway and miR-421 participated in the regulation of ACE2. Thus, ACE2 may contribute to the development of vascular remodeling under conditions of mechanical stretch. Mechanical stretch may decrease the level of the protective factor ACE2 via the p38 MAPK/ATF3 pathway by prompting ATF3 translocation into the nucleus, which could directly bind to the ACE2 promoter via post-transcriptional regulation by miR-421.
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影响因子：
29
作者：
Pan, Xuebo;Shao, Yihui;Lin, Zhuofeng
通讯作者：
Lin, Zhuofeng
DOI：
10.1124/jpet.112.195446
发表时间：
2012-11-01
影响因子：
3.5
作者：
Cai, Yujun;Knight, Walter E.;Yan, Chen
通讯作者：
Yan, Chen
机械应力和高级糖基化终产物诱导的蛋白质二硫键异构酶介导的血管平滑肌细胞凋亡和增殖导致糖尿病小鼠静脉移植物动脉粥样硬化
影响因子：
9
作者：
Ping S;Liu S;Zhou Y;Li Z;Li Y;Liu K;Bardeesi AS;Wang L;Chen J;Deng L;Wang J;Wang H;Chen D;Zhang Z;Sheng P;Li C
通讯作者：
Li C
肾素-血管紧张素系统的 ACE2/血管紧张素 1-7 轴在心力衰竭中的作用。
影响因子：
20.1
作者：
Patel VB;Zhong JC;Grant MB;Oudit GY
通讯作者：
Oudit GY
影响因子：
10.8
作者：
Cheng, Wen-Pin;Wang, Bao-Wei;Shyu, Kou-Gi
通讯作者：
Shyu, Kou-Gi