The effect of inorganic arsenic on endothelium-dependent relaxation: role of NADPH oxidase and hydrogen peroxide.
The effect of inorganic arsenic on endothelium-dependent relaxation: role of NADPH oxidase and hydrogen peroxide.
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DOI：
10.1016/j.tox.2013.01.019
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发表时间：
2013-04-05
期刊：
影响因子：
4.5
通讯作者：
Griffith, Tudor M.
中科院分区：
文献类型：
--
作者：
Edwards, David H.;Li, Yiwen;Ellinsworth, David C.;Griffith, Tudor M.
慢性砷摄入易导致血管疾病，但其潜在机制尚不清楚。在本研究中，我们分析了短期亚砷酸盐暴露对血管功能和内皮依赖性松弛的影响。用G蛋白偶联受体激动剂乙酰胆碱(ACh)和环片阿魏酸(CPA)研究兔髂动脉和主动脉环内皮依赖性松弛，一氧化氮(NO)和内皮衍生超极化因子(EDHF)型，后者通过抑制内皮细胞SERCA泵促进钙内流。用二氢乙锭显像法测定兔主动脉瓣叶内皮细胞、去内皮RIA和主动脉环内皮细胞内ROS的生成。在髂动脉，暴露于100Mμ亚砷酸盐30min可增强CPA和ACh引起的EDH型松弛。过氧化氢酶、模拟过氧化氢酶/超氧化物歧化酶的锰卟啉和NADPH氧化酶抑制剂apocynin可以阻止这种增强。相比之下，在表现出可忽略的EDHF类型反应的主动脉环中，CPA和ACh引起的内皮依赖的NO介导的松弛不受亚砷酸盐的影响。亚砷酸盐可使主动脉瓣内皮细胞产生的ROS对亚砷酸盐敏感，但对髂动脉和主动脉的中膜和外膜无明显影响。我们的结果表明，亚砷酸盐可以通过依赖于过氧化氢的机制来增强EDHF类型的松弛，从而证明了在eNOS活性降低的情况下，NADPH氧化酶产生的超氧阴离子的歧化可以潜在地抵消NO生物可利用性的损失。相比之下，暴露于亚砷酸盐后内皮细胞ROS产生的选择性增加未能改变内源性NO介导的松弛。
Chronic arsenic ingestion predisposes to vascular disease, but underlying mechanisms are poorly understood. In the present study we have analyzed the effects of short-term arsenite exposure on vascular function and endothelium-dependent relaxation. Endothelium-dependent relaxations, nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF)-type, were studied in rabbit iliac artery and aortic rings using the G protein-coupled receptor agonist acetylcholine (ACh) and by cyclopiazonic acid (CPA), which promotes store-operated Ca2+ entry by inhibiting the endothelial SERCA pump. Production of reactive oxygen species (ROS) in the endothelium of rabbit aortic valve leaflets and endothelium-denuded RIA and aortic rings was assessed by imaging of dihydroethidium. In the iliac artery, exposure to 100 μM arsenite for 30 min potentiated EDHF-type relaxations evoked by both CPA and ACh. Potentiation was prevented by catalase, the catalase/superoxide dismutase mimetic manganese porphyrin and the NADPH oxidase inhibitor apocynin. By contrast in aortic rings, that exhibited negligible EDHF-type responses, endothelium-dependent NO-mediated relaxations evoked by CPA and ACh were unaffected by arsenite. Arsenite induced apocynin-sensitive increases in ROS production in the aortic valve endothelium, but not in the media and adventitia of the iliac artery and aorta. Our results suggest that arsenite can potentiate EDHF-type relaxations via a mechanism that is dependent on hydrogen peroxide, thus demonstrating that dismutation of the superoxide anion generated by NADPH oxidase can potentially offset loss of NO bioavailability under conditions of reduced eNOS activity. By contrast, selective increases in endothelial ROS production following exposure to arsenite failed to modify relaxations mediated by endogenous NO.
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DOI：
10.1073/pnas.0408919102
发表时间：
2005-05-10
影响因子：
11.1
作者：
Griffith, TM;Chaytor, AT;Edwards, DH
通讯作者：
Edwards, DH
影响因子：
4.8
作者：
Hu, QH;Zheng, GM;Ziegelstein, RC
通讯作者：
Ziegelstein, RC
影响因子：
10.8
作者：
GRIFFITH, TM;EDWARDS, DH;HENDERSON, AH
通讯作者：
HENDERSON, AH
影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
Harrison, DG
影响因子：
3.9
作者：
Day, BJ;Fridovich, I;Crapo, JD
通讯作者：
Crapo, JD