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J Thorac Cardiovasc Surg 2009;137:471-480
© 2009 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice

Denis Angoulvant, MD, PhD, Shafie Fazel, MD, PhD, Richard D. Weisel, MD, Teresa Y.Y. Lai, MSc, Paul W. Fedak, MD, PhD, Liwen Chen, MSc, Shahin Rafati, MD, MSc, Charit K. Seneviratne, PhD, Norbert Degousee, PhD, Ren-Ke Li, MD, PhD*

Division of Cardiovascular Surgery, Toronto General Research Institute, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Received for publication June 17, 2008; revisions received July 25, 2008; accepted for publication August 16, 2008.

* Address for reprints: Ren-Ke Li, MD, PhD, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College St, Toronto, Ontario, Canada, M5G 1L7. (Email: renkeli{at}uhnres.utoronto.ca).

Objective: Cell-based gene therapy can enhance the effects of cell transplantation by temporally and spatially regulating the release of the gene product. The purpose of this study was to evaluate transient matrix metalloproteinase inhibition by implanting cells genetically modified to overexpress a natural tissue inhibitor of matrix metalloproteinases (tissue inhibitor of matrix metalloproteinase-3) into the hearts of mutant (tissue inhibitor of matrix metalloproteinase-3–deficient) mice that exhibit an exaggerated response to myocardial infarction. Following a myocardial infarction, tissue inhibitor of matrix metalloproteinase-3–deficient mice undergo accelerated cardiac dilatation and matrix disruption due to uninhibited matrix metalloproteinase activity. This preliminary proof of concept study assessed the potential for cell-based gene therapy to reduce matrix remodeling in the remote myocardium and facilitate functional recovery.

Methods: Anesthetized tissue inhibitor of matrix metalloproteinase-3–deficient mice were subjected to coronary ligation followed by intramyocardial injection of vector-transfected bone marrow stromal cells, bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3, or medium. Functional, morphologic, histologic, and biochemical studies were performed 0, 3, 7, and 28 days later.

Results: Bone marrow stromal cells and bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 significantly decreased scar expansion and ventricular dilatation 28 days after coronary ligation and increased regional capillary density to day 7. Only bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 reduced early matrix metalloproteinase activities and tumor necrosis factor {alpha} levels relative to medium injection. Bone marrow stromal cells overexpressing tissue inhibitor of matrix metalloproteinase-3 were also more effective than bone marrow stromal cells in preventing progressive cardiac dysfunction, preserving remote myocardial collagen content and structure, and reducing border zone apoptosis for at least 28 days after implantation.

Conclusions: Tissue inhibitor of matrix metalloproteinase-3 overexpression enhanced the effects of bone marrow stromal cells transplanted early after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice by contributing regulated matrix metalloproteinase inhibition to preserve matrix collagen and improve functional recovery.

Abbreviations List: ADAM = a disintegrin and a metalloproteinase domain; ANOVA = analysis of variance; BMSC = bone marrow stromal cell; ECM = extracellular matrix; ELISA = enzyme-linked immunosorbent assay; FAC = fractional area change; LV = left ventricular; MI = myocardial infarction; MMP = matrix metalloproteinase; TIMP = tissue inhibitor of matrix metalloproteinase; timp3 –/– = TIMP-3-deficient mice; TNF-{alpha} = tumor necrosis factor {alpha}; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling; VEGF = vascular endothelial growth factor






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