Pressure Promotes Angiotensin II–Mediated Migration of Human Coronary Smooth Muscle Cells Through Increase in Oxidative Stress
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Angiotensin II–mediated oxidative stress may play a role in the pathogenesis of coronary atherosclerosis. We examined the effects of pressure on the angiotensin II–mediated increase in oxidative stress and migration of cultured human coronary smooth muscle cells (SMCs). Increased pressure (100 mm Hg) by helium gas for 48 hours increased angiotensin II–mediated oxidative stress as evaluated by flow cytometry and SMC migration (from 15.9±2.2 to 32.0±2.4 cells per 4 high-power fields, P<0.05; n=8). The pressure-induced increases in oxidative stress observed appear to involve phospholipase D (PLD) and protein kinase C (PKC), inasmuch as the indirect PLD inhibitor suramin, at 100 μmol/L, and the PKC inhibitor chelerythrine, at 1 μmol/L, completely blocked the increase in angiotensin II–mediated oxidative stress induced by pressure. Pressure-induced increase in angiotensin II–mediated oxidative stress was inhibited by diphenylene iodonium chloride, an NADPH oxidase inhibitor, by 79% (P<0.05, n=8). Losartan (1 μmol/L), its active metabolite E3174 (1 μmol/L), and the antioxidant N-acetylcysteine (100 mmol/L) but not PD123319 (1 μmol/L) also blocked pressure-induced increases in angiotensin II–mediated oxidative stress and SMC migration (P<0.05, n=8). These findings suggest a novel cellular mechanism whereby pressure regulates the angiotensin II–mediated migration of SMCs, possibly via angiotensin II type 1 receptors, and which involves PLD-mediated, PKC-mediated, and NADPH oxidase–mediated increases in oxidative stress.
- Received September 23, 2001.
- Revision received October 29, 2001.
- Accepted November 7, 2001.