Long-Term Angiotensin II Blockade May Improve Not Only Hyperglycemia but Also Age-Associated Cardiac Fibrosis

Abstract

Abstract. In the present study, the effects of long-term angiotensin (Ang) II antagonism on the development of cardiac and endothelial disorders were examined in Spontaneously Diabetic Torii (SDT) rats. Blood glucose concentration started to increase markedly in the untreated SDT rats from 20 weeks of age, while the blood glucose concentrations of candesartan cilexetil-treated SDT rats were significantly lower until 30 weeks of age. Cardiac function deteriorated in SDT rats and was accompanied by severe cardiac fibrosis, cardiac hypertrophy, and microstructural pathologic change in cardiomyocytes. Cardiac function was very well preserved in the agematched Sprague Dawley (SD) rats, but cardiac fibrosis developed with aging. Candesartan cilexetil treatment improved cardiac structural remodeling and cardiac function in SDT rats. Surprisingly, the degree of cardiac fibrosis in candesartan cilexetil-treated SDT rats was less than that of SD rats. Immunohistological staining confirmed that in addition to collagen deposition, fibroblasts and myofibroblasts were the main cellular components in the cardiac fibrotic areas. The diabetic hearts showed positive staining for ACE, Ang II, and AT 1 receptors. SDT rats also showed decreased endothelial function, which was improved with candesartan cilexetil treatment. These findings indicate that Ang II is involved in the development of cardiac dysfunction by accelerating cardiac remodeling and cardiomyocyte damage in the presence of hyperglycemia. On the other hand, although the mechanisms responsible for the cardiac fibrosis that occurs under normal conditions may differ greatly from those responsible for cardiac fibrosis with hyperglycemia, Ang II seems to play an important role in both.

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

“…These findings are in agreement with other studies [26][27][28] . Consistent with their impaired cardiac function, diabetic rats developed myocardial fibrosis, the marked fibrotic regions (as observed by immunohistochemical staining), as well as deposition of collagen fibers in the interstitial spaces among cardiomyocytes (as observed by TEM), our observations are similar to those described in other reports [29,30] . Increased myocardial fibrosis is a major factor responsible for myocardial stiffness and eventual systolic [31,32] .…”

Patterns of Use of Perioperative Angiotensin-Converting Enzyme Inhibitors in Coronary Artery Bypass Graft Surgery With Cardiopulmonary Bypass

“…36,37 Thus, inhibition of the RAAS with ACEIs alone or in combination with angiotensin receptor blockers should be an effective modality for lowering perioperative cardiovascular risks. More recently, the benefits of ACEIs appear to be systemic and independent of its blood pressure effects, providing cerebrovascular and renovascular protection.…”

STAT1/3 and ERK1/2 Synergistically Regulate Cardiac Fibrosis Induced by High Glucose

“…Cardiac fibrosis is one of the major pathological processes of diabetic cardiomyopathy [2] and manifests as enhanced proliferation of cardiac fibroblasts (CFs) and excessive deposition of extracellular matrix (ECM), such as collagens. Hyperglycemia is one of the major pathological manifestations of diabetes and may promote the development of heart failure, primarily by causing excessive accumulation of collagen within the interstices of the myocardium, which can result in impaired diastolic and systolic functions [3,4]. Treatment of cultured CFs with high concentrations of glucose (HG) results in increased proliferation of CFs and collagen synthesis [5,6,7].…”