Published online before print July 19, 2007

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(American Journal of Pathology. 2007;171:777-789.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070056

A Thrombospondin-1 Antagonist of Transforming Growth Factor-ß Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II

Souad Belmadani^*, Juan Bernal^*, Chih-Chang Wei, Manuel A. Pallero, Louis Dell’Italia, Joanne E. Murphy-Ullrich and Kathleen H. Berecek^*

From the Department of Physiology and Biophysics,^* the Department of Pathology and the BioMatrix Engineering and Regenerative Medicine Center, and Department of Medicine, Division of Cardiovascular Medicine, Center for Heart Failure Research, University of Alabama at Birmingham, Birmingham, Alabama

In diabetes and hypertension, the induction of increased transforming growth factor-ß (TGF-ß) activity due to glucose and angiotensin II is a significant factor in the development of fibrosis and organ failure. We showed previously that glucose and angiotensin II induce the latent TGF-ß activator thrombospondin-1 (TSP1). Because activation of latent TGF-ß is a major means of regulating TGF-ß, we addressed the role of TSP1-mediated TGF-ß activation in the development of diabetic cardiomyopathy exacerbated by abdominal aortic coarctation in a rat model of type 1 diabetes using a peptide antagonist of TSP1-dependent TGF-ß activation. This surgical manipulation elevates initial blood pressure and angiotensin II. The hearts of these rats had increased TSP1, collagen, and TGF-ß activity, and cardiac function was diminished. A peptide antagonist of TSP1-dependent TGF-ß activation prevented progression of cardiac fibrosis and improved cardiac function by reducing TGF-ß activity. These data suggest that TSP1 is a significant mediator of fibrotic complications of diabetes associated with stimulation of the renin-angiotensin system, and further studies to assess the blockade of TSP1-dependent TGF-ß activation as a potential antifibrotic therapeutic strategy are warranted.

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