Published online before print February 28, 2002, doi: 10.1161/01.RES.0000013780.77774.75
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Submitted on December 12, 2001
Revised on February 13, 2002
Accepted on February 13, 2002
Cardiac-Specific IGF-1 Expression Attenuates Dilated Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Mice
Sara Welch ;
From the Divisions of Molecular Cardiovascular Biology (S.W., D.P., M.A.S.) and Cardiology (S.W., B.G.), Children's Hospital Research Foundation, Cincinnati, Ohio; Biosource International (E.S.), Hopkinton, Mass; and New York Medical College (S.C., A.M.A., F.L., A.L., J.K., P.A.), Cardiovascular Research Institute, Valhalla, NY.
* To whom correspondence should be addressed. E-mail: sussman{at}heart.chmcc.org.
To test the hypothesis that early interventional treatment with insulin-like growth factor-1 (IGF-1) alleviates subsequent development of dilated cardiomyopathy, cardiac-specific IGF-1 expression was introduced by selective cross-breeding into a transgenic mouse model of heart failure that displays phenotypic characteristics of severe dilation. Hemodynamic, structural, and cellular parameters of the heart were compared between nontransgenic, tropomodulin-overexpressing cardiomyopathic, and the hybrid tropomodulin/IGF-1--overexpressing mice. Beneficial effects of IGF-1 were apparent by multiple indices of cardiac structure and function, including normalization of heart mass, anatomy, hemodynamics, and apoptosis. IGF-1 expression also acted as a proliferative stimulus as evidenced by calculated increases in myocyte number as well as expression of Ki67, a nuclear marker of cellular replication. Cellular analyses revealed that IGF-1 inhibited characteristic cardiomyocyte elongation in dilated hearts and restored calcium dynamics comparable to that observed in normal cells. Collectively, these results provide novel information regarding the ability of IGF-1 to inhibit progression of cardiomyopathic disease in a defined model system and suggest that heart failure may benefit from early interventional IGF-1 treatment.
Key words: heart • dilated cardiomyopathy • insulin-like growth factor • transgenic
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