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Crosstalk between TGF-β/Smad3 and BMP/BMPR2 signaling pathways via miR-17–92 cluster in carotid artery restenosis

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Abstract

In the recent decades, carotid angioplasty and stenting (CAS) has been developed into a credible option for the patients with carotid stenosis. However, restenosis remains a severe and unsolved issue after CAS treatment. Restenosis is characterized by neointimal hyperplasia, which is partially caused by vascular smooth muscle cells (VSMC) proliferation. However, the molecular mechanism involved in the restenosis is still unclear. In this study, we demonstrated a functional crosstalk between two TGF-β superfamily signaling pathway members, Smad3 and BMPR2, in VSMC proliferation. Smad3 plays an important role in the TGF-β/Smad3 signaling pathway, and is significantly upregulated in the carotid artery with restenosis to promote VSMC proliferation. In contrast, BMP receptor II (BMPR2), an inhibitor of VSMC proliferation is downregulated in carotid restenosis. We further found that BMPR2 downregulation is mediated by miR-17–92 cluster, which is transcriptionally regulated by Smad3. Thus, Smad3 upregulation and Smad3/miR-17–92 cluster-dependent BMPR2 downregulation are likely to promote VSMC proliferation and restenosis. Taken together, our results may provide novel clues for early diagnosis of carotid restenosis and developing new therapeutic strategy.

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Acknowledgments

This study was supported by the National Institute of Health (CA132755 and CA130899 to X.Y.), the University of Michigan Cancer Center and GI Peptide Research Center. X.Y. is a recipient of the Era of Hope Scholar Award from the Department of Defense.

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Authors and Affiliations

  1. Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing, China

    Tao Luo & Shijun Cui

  2. Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 West Medical Center Dri, Rm 5556, MSRB-2, Ann Arbor, MI, 48109, USA

    Chunjing Bian & Xiaochun Yu

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  1. Tao Luo
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  2. Shijun Cui
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  3. Chunjing Bian
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  4. Xiaochun Yu
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Correspondence to Chunjing Bian or Xiaochun Yu.

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Tao Luo and Shijun Cui have contributed equally to this work.

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Luo, T., Cui, S., Bian, C. et al. Crosstalk between TGF-β/Smad3 and BMP/BMPR2 signaling pathways via miR-17–92 cluster in carotid artery restenosis. Mol Cell Biochem 389, 169–176 (2014). https://doi.org/10.1007/s11010-013-1938-6

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