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

Chao Ye1, Ying Tong1, Nan Wu1, Guo-wei Wan1, Fen Zheng1, Jing-yu Chen1, Jian-zhen Lei1, Hong Zhou1, Ai-dong Chen1, Jue-jin Wang1, Qi Chen2, Yue-hua Li2, Yu-ming Kang3, Guo-qing Zhu1,2
1 Department of Physiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Nanjing Medical University, Nanjing 211166, China
2 Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China
3 Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine, Xi’an 710061, China
Correspondence to: Guo-qing Zhu:,
DOI: 10.1038/s41401-020-00608-x
Received: 8 September 2020
Accepted: 29 December 2020
Advance online: 15 February 2021


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 inhibited vascular 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.
Keywords: microRNA; FNDC5; hypertension; vascular smooth muscle cells; proliferation; vascular remodeling

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