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Circulation Research. 2001;88:1291-1298
Published online before print June 7, 2001, doi: 10.1161/hh1201.092042
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(Circulation Research. 2001;88:1291.)
© 2001 American Heart Association, Inc.


Integrative Physiology

Diabetes Mellitus Enhances Vascular Matrix Metalloproteinase Activity

Role of Oxidative Stress

Shiro Uemura, Hidetsugu Matsushita, Wei Li, Alexander J. Glassford, Tomoko Asagami, Keun-Ho Lee, David G. Harrison, Philip S. Tsao

From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, Calif, and the Division of Cardiology (D.G.H.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

Correspondence to Philip S. Tsao, PhD, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail ptsao{at}stanford.edu

Abstract

Abstract—Diabetes mellitus (DM) is a primary risk factor for cardiovascular disease. Although recent studies have demonstrated an important role for extracellular matrix metalloproteinases (MMPs) in atherosclerosis, little is known about the effects of hyperglycemia on MMP regulation in vascular cells. Gelatin zymography and Western blot analysis revealed that the activity and expression of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2) gelatinase, were significantly increased in vascular tissue and plasma of two distinct rodent models of DM. Bovine aortic endothelial cells (BAECs) grown in culture did not express MMP-9 constitutively; however, chronic (2-week) incubation with high glucose medium induced MMP-9 promoter activity, mRNA and protein expression, and gelatinase activity in BAECs. On the other hand, high glucose culture did not change MMP-9 activity from vascular smooth muscle cells or macrophages. Electron paramagnetic resonance studies indicate that BAECs chronically grown in high glucose conditions produce 70% more ROS than do control cells. Enhanced MMP-9 activity was significantly reduced by treatment with the antioxidants polyethylene glycol–superoxide dismutase and N-acetyl-L-cysteine but not by inhibitors of protein kinase C. In conclusion, vascular MMP-9 activity is increased in DM, in part because of enhanced elaboration from vascular endothelial cells, and oxidative stress plays an important role. This novel mechanism of redox-sensitive MMP-9 expression by hyperglycemia may provide a rationale for antioxidant therapy to modulate diabetic vascular complications.


Key Words: endothelium • atherosclerosis • gelatinase • oxidative stress • remodeling




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