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Deletion of smooth muscle ZFP36 promotes neointimal hyperplasia in mice

Acta Pharmacologica Sinica volume 46, pages 1317–1328 (2025)Cite this article

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.

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Fig. 1: ZFP36 expression is decreased in proliferative VSMCs.
Fig. 2: PDGF-BB inhibits ZFP36 expression through KLF4.
Fig. 3: VSMC-specific deletion of Zfp36 accelerates neointimal formation in mice.
Fig. 4: ZFP36 inhibits VSMC proliferation and migration.
Fig. 5: ZFP36 inhibits CEMIP expression by promoting its mRNA decay.
Fig. 6: ZFP36 regulates VSMC proliferation and migration through CEMIP in vitro.
Fig. 7: ZFP36 regulates neointimal hyperplasia through CEMIP in vivo.

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Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request. The RNA-seq datasets have been deposited in the NCBI Gene Expression Omnibus and are accessible through the accession number GSE286906.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 82470499, 82270457, 82300486), the Natural Science Foundation of Shandong Province (ZR2023QH398, ZR2022QH288, ZR2024ZD23), the Taishan Scholar Project of Shandong Province of China (No. tstp20240852), and the Postdoctoral Innovation Project of Shandong Province (SDCX-ZG-202400016).

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  1. These authors contributed equally: Lei Wang, Li-fan He

Authors and Affiliations

  1. State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China

    Lei Wang, Li-fan He, Xiao Xiong, Zhi-nan Wu, Hui-xia Lu, Xiao-ping Ji, Yan-ling Zhang, Wencheng Zhang & Yan Liu

  2. Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China

    Lei Wang & Li-fan He

  3. 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

    Mi Tian

  4. Department of Cardiac Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China

    Guang-qing Cao

  5. Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria

    Pavel Kovarik

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Contributions

YL and WCZ developed and designed the study; LW, LFH, XX, ZNW, MT and YLZ developed the methodology and wrote, reviewed and revised the paper; HXL and XPJ acquired, analyzed, interpreted, and statistically analyzed the data; and GQC and PK provided technical and material support. All the authors read and approved the final paper.

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Correspondence to Wencheng Zhang or Yan Liu.

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Wang, L., He, Lf., Xiong, X. et al. Deletion of smooth muscle ZFP36 promotes neointimal hyperplasia in mice. Acta Pharmacol Sin 46, 1317–1328 (2025). https://doi.org/10.1038/s41401-024-01473-8

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