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

In diabetes and hypertension, the induction of increased transforming growth factor-beta (TGF-beta) activity due to glucose and angiotensin H 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 TSPl-mediated TGF-beta activation in the development of diabetic cardiomyopathy exacerbated by abdominal aortic coarctation in a rat model of type I diabetes using a peptide antagonist of TSPI-dependent TGF-beta activation. This surgical manipulation elevates initial blood pressure and angiotensin H. 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 TSPI 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 TSPI-dependent TGF-13 activation as a potential anti-fibrotic therapeutic strategy are warranted.