Article

Deletion of smooth muscle ZFP36 promotes neointimal hyperplasia in mice

Lei Wang1,2,3,4, Li-fan He1,2,3,4, Xiao Xiong1,2,3, Zhi-nan Wu1,2,3, Mi Tian5, Guang-qing Cao6, Hui-xia Lu1,2,3, Xiao-ping Ji1,2,3, Yan-ling Zhang1,2,3, Pavel Kovarik7, Wencheng Zhang1,2,3, Yan Liu1,2,3
1 State Key Laboratory for Innovation and Transformation of Luobing Theory
2 Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province
3 Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China
4 Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
5 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan 250014, China
6 Department of Cardiac Surgery, Qilu Hospital of Shandong University, Jinan 250012, China
7 Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
Correspondence to: Wencheng Zhang: zhangwencheng@sdu.edu.cn, Yan Liu: 200962000811@sdu.edu.cn,
DOI: 10.1038/s41401-024-01473-8
Received: 10 September 2024
Accepted: 29 December 2024
Advance online: 31 January 2025

Abstract

Platelet-derived growth factor (PDGF-BB) released from the injured intima induces the proliferation and migration of vascular smooth muscle cells (VSMCs), which is the key mechanism of neointimal hyperplasia. Zinc finger 36 (ZFP36), a widespread RNA-binding protein, is important for pathological processes in many diseases. In this study we investigated the role of ZFP36 in VSMCs proliferation, migration and neointimal hyperplasia in mice. We generated smooth muscle-specific Zfp36 knockout (Zfp36SMKO) mice, and established restenosis mouse models by ligation of left carotid artery in Zfp36SMKO mice. We showed that the expression levels of ZFP36 were significantly decreased in human atherosclerotic coronary arteries and murine injured carotid arteries compared with controls. Compared to control Zfp36fl/fl mice, Zfp36SMKO mice displayed accelerated neointimal hyperplasia. In cultured mouse VSMCs, PDGF-BB (20 ng/mL) significantly downregulated ZFP36 expression through KLF4 binding site in Zfp36 promoter. We revealed that ZFP36 could bind to the mRNA of cell migration-inducing protein (CEMIP) and promoted its degradation in VSMCs, thereby reducing the expression of CEMIP protein. Knockdown of Cemip inhibited VSMCs proliferation and migration induced by Zfp36 knockout, thereby suppressing neointimal hyperplasia in Zfp36SMKO mice. We conclude that vascular smooth muscle ZFP36 has a protective effect against neointimal hyperplasia by reducing CEMIP expression. ZFP36 is downregulated by vascular injury and PDGF-BB treatment, which promotes VSMCs proliferation and migration and neointima formation. The results suggest that targeting ZFP36 may represent a novel therapeutic strategy for preventing or treating neointimal hyperplasia and related cardiovascular diseases.

Keywords: neointimal hyperplasia; vascular smooth muscle; platelet-derived growth factor; ZFP36; CEMIP

Article Options

Download Citation

Cited times in Scopus