Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression.

Abstract

Vascular smooth muscle cells (VSMCs) proliferate in response to arterial injury. Recent findings suggest that, in addition to platelet-derived growth factors, growth factors from inflammatory cells and endothelial cells at the site of injury may contribute to VSMC proliferation. We hypothesized that a common mechanism by which endothelial cells and inflammatory cells stimulate VSMC growth could be the active oxygen species (i.e., 02, H202, and OH) generated during arterial injury. Using xanthine/ xanthine oxidase to generate active oxygen species, we studied the effects of these agents on VSMC growth. Xanthine/xanthine oxidase (100 ,M xanthine and 5 microunits/ml xanthine oxidase) stimulated DNA synthesis in growth-arrested VSMCs by 180%o over untreated cells. All tissues are constantly exposed to exogenous and endogenous oxidants.4"15 Vascular endothelial cells exhibit metabolic activities that may produce high concentrations of active oxygen species.16-'8 In fact, the physiological production of endothelium-derived relaxing factor necessarily involves generation of active oxygen species. Active oxygen species concentrations are increased in blood vessels and myocardium in response to a variety of injury-related conditions such as ischemia, thrombosis and reperfusion, and angioplasty.19'20 These same circumstances frequently are associated with intimal hyperplasia and accelerated atherosclerosis. Therefore, there may be a relation between arterial injury, active oxygen species production, and VSMC proliferation. To test this hypothesis, we studied the effects of active oxygen species on VSMC growth and c-myc and c-fos mRNA levels.2",22 In this work, we show that H202 specifically stimulates VSMC DNA synthesis and protooncogene expression. Materials and Methods Cell CultureVSMCs were isolated from the thoracic aortas of 200-250-g male Sprague-Dawley rats by enzymatic dissociation as described previously.5'6 Cells were grown in Dulbecco's modified Eagle's medium (DME) supplemented with 10% (vol/vol) heat-inactivated calf serum, 100 units/ml penicillin, and 100 ,ug/ml streptomycin.The cultures were maintained in humidified 95%

Selective Induction of Heparin-binding Epidermal Growth Factor-like Growth Factor by Methylglyoxal and 3-Deoxyglucosone in Rat Aortic Smooth Muscle Cells

“…ROS activate cellular growth and play a significant role in tumor promotion and degenerative diseases (49,50). A previous report indicates that ROS specifically stimulate the growth of vascular smooth muscle cells but not endothelial cells or fibroblasts (51). Our study indicates that oxidative stress is involved in MG and 3-DG-induced HB-EGF mRNAs.…”

Hydrogen peroxide as a potent activator of T lymphocyte functions

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Overexpression of heme oxygenase-1 protects smooth muscle cells against oxidative injury and inhibits cell proliferation

“…It is reported that active oxygen species is not only harmful to vascular cells, but also might be act as stimuli to VSMC growth [29]. Since the VSMC were supposed to migrate from medial layer into the new-grown intima and are rapidly proliferated as consequence of endothelial damage, therefore it has been believed that accumulation of immigrant VSMC play an important role for the initiation of atherosclerosis.…”