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A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II.

Authors: Belmadani, S  Bernal, J  Wei, CC  Pallero, MA  Dell'italia, L  Murphy-Ullrich, JE  Berecek, KH 
Citation: Belmadani S, etal., Am J Pathol. 2007 Sep;171(3):777-89. Epub 2007 Jul 19.
Pubmed: (View Article at PubMed) PMID:17640965
DOI: Full-text: DOI:10.2353/ajpath.2007.070056

In diabetes and hypertension, the induction of increased transforming growth factor-beta (TGF-beta) 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-beta activator thrombospondin-1 (TSP1). Because activation of latent TGF-beta is a major means of regulating TGF-beta, we addressed the role of TSP1-mediated TGF-beta 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-beta activation. This surgical manipulation elevates initial blood pressure and angiotensin II. The hearts of these rats had increased TSP1, collagen, and TGF-beta activity, and cardiac function was diminished. A peptide antagonist of TSP1-dependent TGF-beta activation prevented progression of cardiac fibrosis and improved cardiac function by reducing TGF-beta 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-beta activation as a potential antifibrotic therapeutic strategy are warranted.

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CRRD Object Information
CRRD ID: 2317942
Created: 2010-04-30
Species: All species
Last Modified: 2010-04-30
Status: ACTIVE



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