Inhibition of miR-135a-5p attenuates vascular smooth muscle cell proliferation and vascular remodeling in hypertensive rats.

Chao Ye,Hong Zhou,Qi Chen,Fen Zheng,Guo-Qing Zhu,Yu-Ming Kang,Ai-Dong Chen,Ying Tong,Guo-Wei Wan,Nan Wu,Jing-Yu Chen,Yue-Hua Li,Jian-Zhen Lei,Jue-Jin Wang

doi:10.1038/s41401-020-00608-x

Abstract

Proliferation of vascular smooth muscle cells (VSMCs) greatly contributes to vascular remodeling in hypertension. This study is to determine the roles and mechanisms of miR-135a-5p intervention in attenuating VSMC proliferation and vascular remodeling in spontaneously hypertensive rats (SHRs). MiR-135a-5p level was raised, while fibronectin type III domain-containing 5 (FNDC5) mRNA and protein expressions were reduced in VSMCs of SHRs compared with those of Wistar-Kyoto rats (WKYs). Enhanced VSMC proliferation in SHRs was inhibited by miR-135a-5p knockdown or miR-135a-5p inhibitor, but exacerbated by miR-135a-5p mimic. VSMCs of SHRs showed reduced myofilaments, increased or even damaged mitochondria, increased and dilated endoplasmic reticulum, which were attenuated by miR-135a-5p inhibitor. Dual-luciferase reporter assay shows that FNDC5 was a target gene of miR-135a-5p. Knockdown or inhibition of miR-135a-5p prevented the FNDC5 downregulation in VSMCs of SHRs, while miR-135a-5p mimic inhibited FNDC5 expressions in VSMCs of both WKYs and SHRs. FNDC5 knockdown had no significant effects on VSMC proliferation of WKYs, but aggravated VSMC proliferation of SHRs. Exogenous FNDC5 or FNDC5 overexpression attenuated VSMC proliferation of SHRs, and prevented miR-135a-5p mimic-induced enhancement of VSMC proliferation of SHR. MiR-135a-5p knockdown in SHRs attenuated hypertension, normalized FNDC5 expressions and inhibitedvascular smooth muscle proliferation, and alleviated vascular remodeling. These results indicate that miR-135a-5p promotes while FNDC5 inhibits VSMC proliferation in SHRs. Silencing of miR-135a-5p attenuates VSMC proliferation and vascular remodeling in SHRs via disinhibition of FNDC5 transcription. Either inhibition of miR-135a-5p or upregulation of FNDC5 may be a therapeutically strategy in attenuating vascular remodeling and hypertension.

Highlights

Vascular smooth muscle cells (VSMCs) are the main cell components of the media of arteries
The miR-135a-5p inhibitor showed inhibitory effects similar to those of miR-135a5p siRNA (Supplementary Fig. S2), and the miR-135a-5p mimic promoted the VSMC proliferation in the spontaneously hypertensive rats (SHRs) (Fig. 1b). These treatments had no significant effects on the VSMC proliferation in the Wistar–Kyoto rats (WKYs). These results indicate that miR-135a5p promotes VSMC proliferation in SHRs and that endogenous miR-135a-5p at least partially contributes to the enhanced VSMC proliferation in SHRs
We have shown that miR-155-5p inhibits VSMC proliferation by inhibiting angiotensinconverting enzyme (ACE) expression in SHRs [9]

Summary

Introduction

Vascular smooth muscle cells (VSMCs) are the main cell components of the media of arteries. VSMC proliferation plays pivotal roles in arterial stiffness and vascular remodeling in a variety of vascular diseases, including hypertension, atherosclerosis, restenosis after angioplasty or bypass, transplantation arteriopathy, and diabetic vascular complications [1, 2]. Reversing the vascular remodeling associated with hypertension is important for preventing the progression of hypertension [4]. Recent studies in our lab have shown that miR-155-5p in the extracellular vesicles-derived from adventitial fibroblasts (AFs) attenuates VSMC proliferation by inhibiting angiotensinconverting enzyme (ACE) expression in spontaneously hypertensive rats (SHRs) [9, 10]. It has been shown that miR-135a-5p promotes the proliferation of lung cancer cells [11] and human adipose-derived mesenchymal stem cells [12] but inhibits the proliferation of neck squamous cell carcinoma cells [13] and thyroid carcinoma cells [14]. The role of miR-135a-5p in VSMC proliferation is still unknown

Methods

Results

Conclusion