Wen Juan, Tang Baiyi, Guo Lan, Chen Wei, Tang Xiaohong
Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
School of Medicine, Hunan Normal University, Changsha 410081, China.
Int J Hypertens. 2023 Jul 20;2023:9497716. doi: 10.1155/2023/9497716. eCollection 2023.
It has been shown that miR-145 is involved in the differentiation of vascular smooth muscle cells (VSMCs) and may regulate vascular remodeling. However, the molecular mechanisms behind these pathological processes in hypertension are not fully elucidated. The present study was to examine whether miR-145 modulates phenotypic transformation of VSMCs under normal state and synthetic state and to explore the possible role of ADAM17-mediated ACE2 shedding and ACE2-Ang-(1-7)-Mas receptor axis. Wistar rats were fed with high-sucrose/high-fat diet for 30 weeks to establish a metabolic hypertension animal model. VSMCs were cultured and treated with Ang II with or without miR-145 mimics or miR-145 inhibitor. Results showed the expression of contractile markers -SMA and SM22, miR-145, ACE2, and Mas receptor reduced in the thoracic aorta of metabolic hypertensive rats (MHRs), while that of synthetic marker OPN increased as compared to the control group. In in vitro study, miR-145 inhibitor inhibited the expression of -SMA, SM22, ACE2, Mas receptor, and the Ang-(1-7) excretion and induced the expression of synthetic markers OPN, EREG, and MMP2. However, miR-145 mimic produced opposite effects on the VSMCs. In addition, in the synthetic VSMC induced by Ang II, miR-145 inhibitor partially reversed the induced expression of OPN, EREG, and MMP2 by Ang II, while further decreasing the expression of -SMA and SM22 and ACE2-Ang-(1-7)-Mas receptor. Cotreatment with ADAM17 siRNA partially reversed the inducible effect of miR-145 inhibitor on the EREG and MMP2, induced Ang-(1-7) excretion, and upregulated ACE2 and Mas receptor expression. In conclusion, miR-145 alleviates phenotype transition from contractile to synthetic type via ADAM17-mediated ACE2 shedding in VSMCs and retains the activation of ACE2-Ang-(1-7)-Mas axis, which may benefit the vascular structural remodeling in the metabolic hypertension.
研究表明，miR-145参与血管平滑肌细胞（VSMC）的分化，并可能调节血管重塑。然而，高血压这些病理过程背后的分子机制尚未完全阐明。本研究旨在检测miR-145在正常状态和合成状态下是否调节VSMC的表型转化，并探讨ADAM17介导的ACE2脱落和ACE2-Ang-(1-7)-Mas受体轴的可能作用。将Wistar大鼠用高糖/高脂饮食喂养30周以建立代谢性高血压动物模型。培养VSMC并用Ang II处理，同时加入或不加入miR-145模拟物或miR-145抑制剂。结果显示，与对照组相比，代谢性高血压大鼠（MHR）胸主动脉中收缩标志物α-SMA和SM22、miR-145、ACE2和Mas受体的表达降低，而合成标志物OPN的表达增加。在体外研究中，miR-145抑制剂抑制α-SMA、SM22、ACE2、Mas受体的表达以及Ang-(1-7)的分泌，并诱导合成标志物OPN、EREG和MMP2的表达。然而，miR-145模拟物对VSMC产生相反的作用。此外，在由Ang II诱导的合成型VSMC中，miR-145抑制剂部分逆转了Ang II诱导的OPN、EREG和MMP2的表达，同时进一步降低α-SMA和SM22以及ACE2-Ang-(1-7)-Mas受体的表达。与ADAM17 siRNA共同处理部分逆转了miR-!45抑制剂对EREG和MMP2的诱导作用，诱导了Ang-(1-7)的分泌，并上调了ACE2和Mas受体的表达。总之，miR-145通过ADAM17介导的VSMC中ACE2脱落减轻从收缩型到合成型的表型转变，并维持ACE2-Ang-(1-7)-Mas轴的激活，这可能有利于代谢性高血压中的血管结构重塑。
