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J Thorac Cardiovasc Surg 2005;130:1430-1439
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Cell transplantation preserves matrix homeostasis: A novel paracrine mechanism

^a Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada
^b Division of Cardiology, University of Toronto, Roy and Ann Foss Research Program, Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Ontario, Canada

Read at the C. Walton Lillehei Resident Forum at the Eighty-fifth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.

Received for publication March 25, 2005; revisions received May 14, 2005; accepted for publication May 19, 2005.

^_* Address for reprints: Paul W. M. Fedak, MD, PhD, Toronto General Hospital, NU 1-115B, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada (Email: paul.fedak{at}utoronto.ca).

OBJECTIVES: Cell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation.

METHODS: Smooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (¹⁴C-proline uptake).

RESULTS: Left ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% ± 42% of CON, P = .02; TIMP-3, 118% ± 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% ± 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% ± 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation.

CONCLUSIONS: These data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis.

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