A thrombospondin-1 antagonist of transforming growth factor-beta 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 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.
Belmadani
Souad
S
Department of Physiology and Biophysics, University of Alabama at Birmingham, 668 Volker Hall, 1530 3rd Ave. South, Birmingham, AL 35294-0019, USA.
Bernal
Juan
J
Wei
Chih-Chang
CC
Pallero
Manuel A
MA
Dell'italia
Louis
L
Murphy-Ullrich
Joanne E
JE
Berecek
Kathleen H
KH
D000804:Angiotensin II / Q000097:blood*; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D006439:Hemodynamics; D006801:Humans; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D051899:Smad2 Protein / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
C487834:Leu-Ser-Lys-Leu peptide; D010455:Peptides; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II