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Research ArticleCardiovascular

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

Yujun Cai, Walter E. Knight, Shujie Guo, Jian-Dong Li, Peter A. Knight and Chen Yan
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 479-488; DOI: https://doi.org/10.1124/jpet.112.195446
Yujun Cai
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Walter E. Knight
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Shujie Guo
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Jian-Dong Li
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Peter A. Knight
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Chen Yan
Aab Cardiovascular Research Institute and Department of Medicine (Y.C., W.E.K., C.Y.) and Department of Surgery (P.A.K.), University of Rochester, Rochester, New York; Shanghai Key Laboratory of Vascular Biology at Ruijing Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (S.G., C.Y.); and Center for Inflammation, Immunity, and Infection and Department of Biology, Georgia State University, Atlanta, Georgia (J.-D.L.)
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Abstract

Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G1-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.

Footnotes

  • This research was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL077789; HL088400] (to C.Y.); the American Heart Association [Grant 0740021N] (to C.Y.); and a Shanghai Oriental Scholarship (to C.Y.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195446.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    SMC
    smooth muscle cell
    VSMC
    vascular SMC
    3D
    three-dimensional
    AKT
    protein kinase B
    p-AKT
    phosphorylated AKT
    BrdU
    bromodeoxyuridine
    DAPI
    4,6-diamidino-2-phenylindole
    DCFH2-DA
    dichlorodihydrofluorecein diacetate
    DMEM
    Dulbecco's modified Eagle's medium
    ECM
    extracellular matrix
    ERK1/2
    extracellular signal-regulated kinase 1/2
    p-ERK
    phosphorylated ERK
    FBS
    fetal bovine serum
    FGF
    fibroblast growth factor
    IKK
    IκB kinase
    LCA
    left carotid artery
    NAC
    N-acetyl-l-cysteine
    PBS
    phosphate-buffered saline
    PCNA
    proliferating cell nuclear antigen
    PCR
    polymerase chain reaction
    PDE1
    phosphodiesterase 1
    PDGF
    platelet-derived growth factor
    ROS
    reactive oxygen species
    SRB
    sulforhodamine-B
    SV
    saphenous vein
    Vinp
    vinpocetine.

  • Received April 13, 2012.
  • Accepted August 16, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleCardiovascular

Vinpocetine Inhibits Pathological Vascular Remodeling

Yujun Cai, Walter E. Knight, Shujie Guo, Jian-Dong Li, Peter A. Knight and Chen Yan
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 479-488; DOI: https://doi.org/10.1124/jpet.112.195446

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Research ArticleCardiovascular

Vinpocetine Inhibits Pathological Vascular Remodeling

Yujun Cai, Walter E. Knight, Shujie Guo, Jian-Dong Li, Peter A. Knight and Chen Yan
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 479-488; DOI: https://doi.org/10.1124/jpet.112.195446
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