Hypoxic modulation of Ca2+ signaling in human venous endothelial cells -: Multiple roles for reactive oxygen species

被引:43
作者
Aley, PK
Porter, KE
Boyle, JP
Kemp, PJ
Peers, C [1 ]
机构
[1] Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England
[2] Univ Cardiff, Sch Biosci, Cardiff CF10 3US, S Glam, Wales
关键词
D O I
10.1074/jbc.M413674200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The effects of hypoxia (pO(2) similar to 25 mm Hg) on Ca2+ signaling stimulated by extracellular ATP in human saphenous vein endothelial cells were investigated using fluorimetric recordings from Fura-2 loaded cells. In the absence of extracellular Ca2+, ATP-evoked rises of cytosolic Ca2+ concentration ([Ca2+](i)) because of mobilization from the endoplasmic reticulum ( ER). These responses were reduced by prior exposure to hypoxia but potentiated during hypoxia. Hypoxia itself liberated Ca2+ from the ER, but unlike the effects of ATP this effect was not inhibited by blockade of the inositol trisphosphate receptor. By contrast, ryanodine blocked the effects of hypoxia but not those of ATP. Antioxidants abolished the effects of hypoxia but potentiated the effects of ATP. Inhibition of NADPH oxidase also augmented ATP-evoked responses but was without effect on hypoxia-evoked rises of [Ca2+](i). However, either uncoupling mitochondrial electron transport or inhibiting complex I markedly suppressed the actions of hypoxia yet exerted only small inhibitory effects on ATP-evoked rises of [Ca2+](i). Both hypoxia and ATP were able to activate capacitative Ca2+ entry. Our results indicate that hypoxia regulates intracellular Ca2+ signaling via two distinct pathways. First, it modulates agonist-evoked liberation of Ca2+ from the ER primarily through regulation of reactive oxygen species generation from NADPH oxidase. Second, it liberates Ca2+ from the ER via ryanodine receptors, an effect requiring mitochondrial reactive oxygen species generation. These findings suggest that local O-2 tension is a major determinant of Ca2+ signaling in the vascular endothelium, a finding that is likely to be of both physiological and pathophysiological importance.
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页码:13349 / 13354
页数:6
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