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

摘要

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.