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

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2007 Jul 21

PMID 17640965

Citations 70

Authors

Souad Belmadani

Juan Bernal

Chih-Chang Wei

Manuel A Pallero

Louis DellItalia

Joanne E Murphy-Ullrich

Kathleen H Berecek

Affiliations

Soon will be listed here.

Abstract

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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