Diabetic cardiomyopathy, characterized by myocyte hypertrophy and interstitial fibrosis, is a potentially life-threatening complication resulting from lack of glycemic control. Hypertension associated with diabetes increases disease severity. TGF-beta is the primary effector of fibrosis in response to hyperglycemia. Bioactivation of latent TGF-beta is a major regulatory step in controlling TGF-beta and a logical point for therapeutic intervention. Yet, regulation of TGF-beta bioactivity in these diseases is not well understood. The platelet/matrix protein, thrombospondin l (TSP 1), is a physiologic regulator of latent TGF-beta activation. TSP 1 regulates glucose-stimulated increases in TGF-beta bioactivity and matrix protein synthesis in mesangial cells. TSP-dependent TGF-beta activation is also important for the diabetic myocardium, since high glucose stimulates TSP1 and TGF-beta bioactivity in rat cardiac fibroblasts and increases in TGF-beta bioactivity are blocked with TSP antagonist peptides. Similarly, data show that angiotensin II (Ang 11)-stimulates increased TSP 1 expression and TGF-beta bioactivity that can be blocked by addition of the antagonist peptides. Both glucose and Ang II up-regulate TSP 1 expression, potentially through modulation of PKC and nitric oxide (NO). These data support the hypothesis that glucose-mediated modulation of PKC, NO, ROS, and Ang II are involved in the regulation of TSP1 expression, leading to latent TGF-beta activation, matrix protein synthesis, and myocardial fibrosis. In this proposal, we will use a cultured cardiac fibroblast system to determine 1) the interrelationships between glucose, PKC activity, and oxidative balance in regulation of TSP 1 expression, TGF-beta bioactivity, and matrix protein synthesis and; 2) the role of Ang II in regulation of TSP 1-dependent TGF-beta activation and its relation to glucose stimulation. In addition, rats with diabetes (streptozotocin) and hypertensive diabetes will be used to determine 3) whether peptide antagonists of TSP-mediated TGF-beta activation ameliorate diabetic myocardial fibrosis under normo- and hypertensive conditions. These studies will further our understanding of how TGF-beta is regulated in diabetes and hypertension, and will potentially identify new strategies for therapeutically attenuating myocardial fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060658-02
Application #
6620172
Study Section
Pathology A Study Section (PTHA)
Program Officer
Jones, Teresa L Z
Project Start
2002-02-01
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
2
Fiscal Year
2003
Total Cost
$284,130
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294