Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Abstract

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-β 1 (TGF-β 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-β 1 .