Pressure promotes angiotensin II-mediated migration of human coronary smooth muscle cells through increase in oxidative stress

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 mumol/L, and the PKC inhibitor chelerythrine, at 1 mumol/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.