Obesity and
insulin resistance confer increased risk for accelerated
coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of
angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular
fibrosis in genetically obese mice that develop
insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of
angiotensin II (Ang) II. Genetically obese ob/ob mice were given
ACE inhibitor (
temocapril) or Ang II type 1 (AT(1)) receptor blocker (
olmesartan) from 10 to 20 weeks. Cardiac expressions of
plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and
transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary
fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of
PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary
fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular
collagen as measured by
hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular
type 1 collagen. Markedly increased
PAI-1 and
TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with
temocapril or
olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular
fibrosis, plasma
PAI-1 and TGF-beta(1), left ventricular
collagen and mural immunoreactivity for
PAI-1,
TGF-beta and
collagen type 1. The c-Jun NH(2)-terminal
kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by
temocapril and
olmesartan. Ang II-mediated upregulation of
PAI-1 and TGF-beta(1) with
collagen deposition may explain the mechanism of perivascular
fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular
fibrosis and
collagen deposition even before development of overt diabetes. JNK activation may be a mediator of
obesity-related cardiac dysfunction and a potential therapeutic target.