miR-145 Alleviates Smooth Muscle Cell Phenotype Transition via ADAM17-Mediated ACE2 Shedding

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 & alpha;-SMA and SM22 & alpha;, 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 & alpha;-SMA, SM22 & alpha;, 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 & alpha;-SMA and SM22 & alpha; 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.

Automated summary

This study aimed to investigate the regulatory effects of miR-145 on phenotypic transformation of vascular smooth muscle cells (VSMCs) and explore the possible roles of ADAM17-mediated ACE2 shedding and ACE2-Ang-(1-7)-Mas receptor axis. The results showed that the expression of contractile markers α-SMA and SM22α, miR-145, ACE2, and Mas receptor was reduced in metabolic hypertensive rats (MHRs), while the expression of synthetic marker OPN increased. In vitro experiments demonstrated that miR-145 inhibitor inhibited the expression of α-SMA, SM22α, ACE2, and Mas receptor, while inducing the expression of synthetic markers OPN, EREG, and MMP2.