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Reduction of PKCβII activity in smooth muscle cells attenuates acute arterial injury

  • Chun Huang
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
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  • Jong Sun Chang
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
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  • Yunlu Xu
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
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  • Qing Li
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
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  • Yu Shan Zou
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
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  • Shi-Fang Yan
    Correspondence
    Corresponding author at: Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, United States. Tel.: +1 212 305 6030; fax: +1 212 305 5337.
    Affiliations
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States
    Search for articles by this author

      Abstract

      Objective

      The ubiquitous enzyme Protein Kinase C (PKC) has been linked to the pathogenesis of vascular injury, but the cell-specific and discrete functions of the βII isoform have yet to be discovered in this setting. Our previous findings demonstrated significantly increased PKCβII in the membrane fraction of injured femoral arteries in wild type (WT) mice and revealed reduction of neointimal expansion in PKCβ−/− mice after acute vascular injury. As PKCβ−/− mice are globally devoid of PKCβ, we established novel transgenic (Tg) mice to test the hypothesis that the action of PKCβII specifically in smooth muscle cells (SMCs) mediates the formation of neointimal lesions in response to arterial injury.

      Methods

      Tg mice expressing SM22α promoter-targeted mouse carboxyl-terminal deletion mutant PKCβII were produced using standard techniques, subjected to femoral artery injury and compared with littermate controls. Smooth muscle cells (SMCs) were isolated from wild type (WT) and Tg mice and exposed to a prototypic stimulus, tumor necrosis factor (TNF)-α. Multiple strategies were employed in vivo and in vitro to examine the molecular mechanisms underlying the specific effects of SMC PKCβII in neointimal expansion.

      Results

      In vivo and in vitro analyses demonstrated that PKCβII activity in SMCs was critical for neointimal expansion in response to arterial injury, at least in part via regulation of ERK1/2, Egr-1 and induction of MMP-9.

      Conclusions

      These data identify the SMC-specific regulatory role of PKCβII in neointimal expansion in response to acute arterial injury, and suggest that targeted inactivation of PKCβII may be beneficial in limiting restenosis via suppression of the neointima-mediating effects of Egr-1 and MMP-9.

      Keywords

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