Diabetes Mellitus Enhances Vascular Matrix Metalloproteinase Activity

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. (Circ Res. 2001;88:1291-1298.)Key Words: endothelium Ⅲ atherosclerosis Ⅲ gelatinase Ⅲ oxidative stress Ⅲ remodeling C ardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). 1,2 Because the onset and progression of complications are delayed in patients with good glycemic control, 3 hyperglycemia is thought to be an important regulator of vascular lesion development. Recent studies indicate that elevated glucose concentrations can induce dysfunction of several intracellular signal transduction cascades, including modulation of protein kinase C (PKC), activation of mitogenactivated protein kinase, generation of reactive oxygen species (ROS), and accumulation of advanced glycation end products (AGEs). 4,5 However, the underlying mechanisms between hyperglycemia and vascular disease remain unclear.Matrix metalloproteinases (MMPs) are members of a family of Zn 2ϩ -and Ca 2ϩ -dependent endopeptidases, which are essential for cellular migration and tissue remodeling in both physiological and pathological conditions. 6 MMPs are secreted by many types of cells as proenzymes. On activation by proteolytic cleavage, activated enzymes are capable of degrading many extracellular matrix components. Because MMPs appear to be involved in monocyte invasion and vascular smooth muscle cell migration, derangement of MMP regulation is considered to be a critical factor in the development of...

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