期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 145, 期 3, 页码 323-333出版社
WILEY
DOI: 10.1038/sj.bjp.0706193
关键词
endothelin-1; oxidative stress; apoptosis; proliferation; NADPH oxidase; caveolin-1
资金
- NCRR NIH HHS [P20 RR015640, P20 RR15640] Funding Source: Medline
- NIA NIH HHS [R03 AG21324-01] Funding Source: Medline
1 Endothelin-1 (ET-1), an endothelium- derived vasoactive peptide, participates in the regulation of endothelial function through mechanisms that are not fully elucidated. This study examined the impact of ET-1 on oxidative stress, apoptosis and cell proliferation in human umbilical vein endothelial cells (HUVEC). HUVECs were challenged for 24 h with ET-1 (10 pM-10 nM) in the absence or presence of the ETB receptor antagonist BQ788 (1 mu M) or the NADPHoxidase inhibitor apocynin (1 mu M). Reactive oxygen species (ROS) were detected using chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated with 4',6'-diamidino-20-phenylindoladihydrochloride staining and by the caspase-3 assay. Cell proliferation was measured by a colorimetric assay. Expression of NADPH oxidase, Akt, pAkt, Bcl-2, Bax, I kappa B, caveolin-1 and eNOS was evaluated by Western blot analysis. 2 ET-1 significantly enhanced ROS generation and cell proliferation following 24-h incubation, both of which were prevented by BQ788 or apocynin, consistentwith the ability of ET-1 to directly upregulate NADPH oxidase. ET-1 itself did not affect apoptosis but attenuated homocysteineinduced apoptosis through anET(B) receptor-mediated mechanism. Western blot analysis indicated that ET-1 alleviated homocysteine (Hcy)-induced apoptosis, likely acting by antagonizing the Hcy-induced decreases in Akt, pAkt, pAkt-to-Akt, Bcl-2-to-Bax ratios and increases in Bax and caveolin-1 expression. Furthermore, ET-1 downregulated expression of caveolin-1 and eNOS, which was attenuated by BQ788 or apocynin. 3 In summary, our results suggest that ET-1 affects oxidative stress, proliferation and apoptosis possibly through ETB, NADPH oxidase, Akt, Bax and caveolin-1-mediated mechanisms.
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