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Cardiovascular Research 2002 56(3):472-478; doi:10.1016/S0008-6363(02)00592-8
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Expression of matrix metalloproteinases in cardiac allograft vasculopathy and its attenuation by anti MMP-2 ribozyme gene transfection

Katsuaki Tsukiokaa, Jun-ichi Suzukib, Minoru Fujimoria, Yuko Wadaa, Kazuhiro Yamauraa, Ken-ichi Itoa, Ryuichi Morishitac, Yasufumi Kanedac, Mitsuaki Isobeb,* and Jun Amanoa

aDepartment of Surgery (II), Shinshu University School of Medicine, Matsumoto, Japan
bDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
cThe Department of Gene Therapy Science, Osaka University, Osaka, Japan

isobemi.cvm{at}tmd.ac.jp

* Corresponding author. Tel.: +81-3-5803-5951; fax: +81-3-5803-0238.

Objective: Proliferation and migration of vascular smooth muscle cells (SMCs) causes intimal thickening during cardiac allograft vasculopathy (CAV). This process requires the degradation or remodeling of extracellular matrix (ECM) surrounding the cells. Imbalance between degradation and accumulation of ECM also contributes to the development of CAV. In this study, we investigated the contribution of matrix metalloprotenases (MMPs), enzymes regulating ECM turnover, to the development of CAV. Methods: Donor hearts from male DBA mice were heterotopically transplanted to male B10.D2 recipient mice, and harvested at days 15 and 30 post transplantation. We examined expression MMP-2, -3, -9 and -13 of graft vessels using immunohistochemistry. To clarify the role of MMP-2 in CAV, anti MMP-2 ribozyme was delivered into donor hearts just before transplantation, mediated by a hemagglutinating virus of Japan–liposome complex to specifically suppress MMP-2 activity. Results: All MMPs were immunopositive in SMCs from the slightly thickened neointima at day 15. In the advanced stage of intimal thickening at day 30, in addition to increased number of SMCs, accumulation of collagenous fibers was observed; expression of MMP-3, -9 and -13 was decreased. In contrast, MMP-2 expression remained distinctly positive throughout the progression of the vascular remodeling. After the gene transfer of MMP-2 ribozyme, luminal occlusion was significantly decreased compared to non-treated allografts [25.0±6.5 vs. 55.1±7.0% (P<0.05)] at day 30 post transplantation. Conclusion: MMP-2 is a principle MMP throughout the progression of the vascular remodeling in CAV. Anti MMP-2 therapy could therefore be one of the candidates for a supplemental therapy for CAV.

KEYWORDS Extracellular matrix; Gene therapy; Remodeling; Smooth muscle; Transplantation


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