Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity.
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.
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
A K M Tarikuz
AK
Zaman
Satoshi
S
Fujii
Daisuke
D
Goto
Tomoo
T
Furumoto
Tetsuya
T
Mishima
Yukihito
Y
Nakai
Jie
J
Dong
Shogo
S
Imagawa
Burton E
BE
Sobel
Akira
A
Kitabatake
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D024042:Collagen Type I / Q000032:analysis / Q000378:metabolism; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology*; D005355:Fibrosis; D006352:Heart Ventricles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D000068557:Olmesartan Medoxomil; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000097:blood / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D024042:Collagen Type I; D007093:Imidazoles; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D013777:Tetrazoles; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil; C055603:temocapril hydrochloride; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9