Role of angiotensin II in altered expression of molecules responsible for coronary matrix remodeling in insulin-resistant diabetic rats

Objective - Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase ( MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin- resistant diabetic rat hearts. Methods and Results - By immunohistochemistry and in situ hybridization, transforming growth factor-beta(1) ( TGF-beta(1)) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor- 1 ( PAI- 1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP- 2 and decreased expression of membrane type- 1 MMP ( MT1- MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining. Conclusions - In addition to upregulation of PAI- 1, downregulation of MMP- 2 and MT1- MMP might play a crucial role in coronary matrix remodeling in insulin- resistant diabetes. These molecules appear to be regulated by angiotensin II via stimulation of TGF-beta(1).