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(Circulation. 2001;103:3123.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Angiotensin-Converting Enzyme Inhibition Attenuates Hypofibrinolysis and Reduces Cardiac Perivascular Fibrosis in Genetically Obese Diabetic Mice

A. K. M. Tarikuz Zaman, MB, BS; Satoshi Fujii, MD, PhD; Hirotumi Sawa, MD, PhD; Daisuke Goto, MD; Naoki Ishimori, MD; Keiko Watano, MD; Takeaki Kaneko, MD; Tomoo Furumoto, MD; Taeko Sugawara, MD; Ichiro Sakuma, MD, PhD; Akira Kitabatake, MD, PhD; Burton E. Sobel, MD

From the Department of Cardiovascular Medicine and the Laboratory of Molecular and Cellular Pathology (H.S.), CREST, Hokkaido University School of Medicine, Sapporo, Japan, and Department of Medicine, University of Vermont, Burlington (B.E.S.).

Correspondence to Burton E. Sobel, MD, Department of Medicine, University of Vermont College of Medicine, Colchester Research Facility, 208 S Park Dr, Colchester, VT 05446. E-mail burton.sobel{at}vtmednet.org

Background—Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.

Methods and Results—To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription–polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.

Conclusions—Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.

Key Words: fibrinolysis • coronary disease • diabetes mellitus • insulin

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