Journal
CARDIOVASCULAR PATHOLOGY
Volume 10, Issue 6, Pages 311-315Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S1054-8807(01)00095-3
Keywords
atherosclerosis; oxidative stress; endothelin-1; smooth muscle cell; endothelial dysfunction
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Atherosclerosis is based on endothelial dysfunction leading to impaired vasomotor function. This is partially due to nitric oxide (NO) depletion caused by oxidative stress. Since the vasoconstrictor endothelin-1 (ET-1) might also be involved in endothelial dysfunction, we investigated whether oxidative stress regulates ET-I expression in vascular smooth muscle cells (VSMC). Human aortic VSMC were treated with H2O2 (200 muM) for up to 8 h. mRNA expression of preproendothelin (prepro-ET) was analyzed by RT-PCR. ET-1 protein and the marker for oxidative stress, 8-isoprostane, were determined by ELISA. Activity of cytosolic phospholipase A2 (cPLA(2)) as an indicator of ET-1 autocrine activity was measured photometrically. Stimulation of VSMC with H2O2 resulted in increased expression of prepro-ET mRNA after 1 h with a maximum after 6 h (fourfold), similar to treatment with angiotensin 11. ET-1 protein was significantly increased by H2O2 treatment with a maximum after 8 h (P < .05). This effect was inhibited by the antioxidants resveratrol (100 muM) and quercetin (50 muM). In quiesced VSMC, incubation with H2O2-conditioned medium resulted in increased cPLA2 activity compared to the controls (P<.05). This activity was partially inhibited by the ETA-receptor antagonist, PD 142893 (10 M), indicating functional ET-1 in the conditioned medium. The presence of oxidative stress in H2O2-treated VSMC was associated by significantly increased formation of 8-isoprostane (P<.05). The data indicate for the first time that oxidative stress increases ET-1 generation and autocrine ET-1 activity in VSMC, a mechanism that might contribute to endothelial dysfunction in atherosclerosis. <(c)> 2001 Elsevier Science Inc. All rights reserved.
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