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-␤ 1 (TGF-␤ 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. Key Words: matrix remodeling Ⅲ matrix metalloproteinases Ⅲ diabetes Ⅲ plasminogen activator inhibitor-1 Ⅲ angiotensin II C ollagen in the normal adult heart serves several important functions, which include providing a supportive structural lattice for cardiomyocytes and coronary vessels and connecting individual myocytes and myofibrillar bundles to integrate individual cardiac contractions. However, a disproportionate increase in collagen accretion or collagen resorption from normal levels can cause defects in the function and supporting structural lattice of the heart. It has been widely known that diabetes is associated with alterations in extracellular matrix (ECM) turnover and regulation. 1 Pathologic remodeling characterized by ECM deposition might contribute to cardiovascular complications that are the leading cause of morbidity and mortality in diabetic patients. 2 Alteration in diastolic filling of the left ventricle (LV) associated with reciprocal changes in the LV collagen gene and accumulation of cardiac collagen in diabetic rats 3,4 suggest that increased interstitial cardiac collagen might cause cardiac fibrosis and result in greater LV stiffness and decreased LV wall compliance, thus leading to diastolic dysfunction and eventual heart failure in diabetes. Conclusions-InClearly, an imbalance between ECM production and degradation must underlie the process of ECM expansion, but these dynamics in the diabetic heart are poorly understood. Matrix metalloproteinases (MMPs) are primarily responsible for the breakdown of ECM proteins such as collagen and elastin, and their activity is tightly regulated by tissue inhibitors of MMPs (TIMPs). 5,6 Recent experimental evidence indicates that expression of MMP-2 and MMP-9 is altered in renal tissues and vasculature fr...

Telmisartan, an angiotensin-II receptor blocker ameliorates cardiac remodeling in rats with dilated cardiomyopathy

“…20 Ang-II also stimulates cardiac collagen production by promoting TGF-b1 synthesis through AT 1 R receptor activation. 21 In addition, AT 1 R activation has a role in the molecular changes associated with coronary matrix remodeling in diabetes. 21 Furthermore, AT 1 R blockade reduces myocardial hypertrophy, decreases myocardial fibrosis and attenuates cardiac remodeling.…”

“…21 In addition, AT 1 R activation has a role in the molecular changes associated with coronary matrix remodeling in diabetes. 21 Furthermore, AT 1 R blockade reduces myocardial hypertrophy, decreases myocardial fibrosis and attenuates cardiac remodeling. 22 Consistent with previous studies, 21,22 we have also observed increased expressions of TGF-b1 and collagen-III mRNA in group V, and these increased mRNA levels were suppressed by telmisartan treatment (Figures 3a-c).…”

“…21 Furthermore, AT 1 R blockade reduces myocardial hypertrophy, decreases myocardial fibrosis and attenuates cardiac remodeling. 22 Consistent with previous studies, 21,22 we have also observed increased expressions of TGF-b1 and collagen-III mRNA in group V, and these increased mRNA levels were suppressed by telmisartan treatment (Figures 3a-c). Taken together with the above reports, these findings suggest that AT 1 R has an important role in cardiac remodeling through expression of TGF-b1 and collagen-III mRNA, and that telmisartan may contribute to the inhibition of cardiac remodeling.…”

Cardiometabolic Determinants of Carotid and Aortic Distensibility From Childhood to Early Adulthood

“…37,38 Insulin resistance and chronic hyperinsulinemia increase the local activity of renin-angiotensin-aldosterone system and expression of angiotensin II receptors in vascular tissue, thus leading to arterial wall hypertrophy and fibrosis. 39,40 Impaired glucose tolerance also enhances nonenzymatic glycation and crosslinking of collagen, leading to stiffening of arteries. 41 These mechanisms may in part underlie the here observed associations between the cardiometabolic risk markers and arterial distensibility.…”

Perspectives of Cell Therapy in Type 1 Diabetes

“…MSC have been shown to differentiate into several cell types, including cardiomyocytes, endothelial cells, neurons, hepatocytes, epithelial cells and adipocytes, characteristics coupled with capacity of self renewal. Chronic hyperglycemia is responsible for myocardial remodelling leading to ventricular dysfunction with hypertrophy and apoptosis of cardiomyocytes, microcirculatory defects, altered extracellular matrix and matrix metalloproteinasis (Jesmin et al, 2003). MSC can induce myogenesis and angiogenesis by different mitogenic, angiogenic and antiapoptotic factors, such as VEGF, IGF-1 and HGF .…”