Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway

Authors

  • Jung-Sun Kim,

    Corresponding author
    1. Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul, South Korea
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  • Il-Kwon Kim,

    Corresponding author
    1. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • Se-Yeon Lee,

    Corresponding author
    1. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • Byeong-Wook Song,

    1. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • Min-Ji Cha,

    1. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • Heesang Song,

    1. Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, Gwangju, South Korea
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  • Eunmi Choi,

    1. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • Soyeon Lim,

    1. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • Onju Ham,

    1. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    2. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • Yangsoo Jang,

    1. Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul, South Korea
    2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • Ki-Chul Hwang

    Corresponding author
    1. Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul, South Korea
    2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
    3. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea
    4. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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These authors contributed equally to this work.

To whom correspondence should be addressed (email kchwang@yuhs.ac).

Abstract

VSMC (vascular smooth muscle cell) proliferation contributes significantly to intimal thickening in atherosclerosis, restenosis and venous bypass graft diseases. Ang II (angiotensin II) has been implicated in VSMC proliferation though the activation of multiple growth-promoting signals. Although TZDs (thiazolidinediones) can inhibit VSMC proliferation and reduce Ang II-induced fibrosis, the mechanism underlying the inhibition of VSMC proliferation and fibrosis needs elucidation. We have used primary cultured rat aortic VSMCs and specific antibodies to investigate the inhibitory mechanism of rosiglitazone on Ang II-induced VSMC proliferation. Rosiglitazone treatment significantly inhibited Ang II-induced rat aortic VSMC proliferation in a dose-dependent manner. Western blot analysis showed that rosiglitazone significantly lowered phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt (also known as protein kinase B), mTOR (mammalian target of rapamycin), p70S6K (70 kDa S6 kinase) and 4EBP1 (eukaryotic initiation factor 4E-binding protein) levels in Ang II-treated VSMCs. In addition, PPAR-α (peroxisome-proliferator-activated receptor α) mRNA increased significantly and CTGF (connective tissue growth factor), Fn (fibronectin) and Col III (collagen III) levels decreased significantly. The results demonstrate that the rosiglitazone directly inhibits the pro-atherosclerotic effect of Ang II on rat aortic VSMCs. It also attenuates Ang II-induced ECM (extracellular matrix) molecules and CTGF production in rat aortic VSMCs, reducing fibrosis. Importantly, PPAR-α activation mediates these effects, in part, through the mTOR-p70S6K and −4EBP1 system.

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