Endothelin 1 activation of endothelin A receptor/NADPH oxidase pathway and diminished antioxidants critically contribute to endothelial progenitor cell reduction and dysfunction in salt-sensitive hypertension.
Endothelin 1 activation of endothelin A receptor/NADPH oxidase pathway and diminished antioxidants critically contribute to endothelial progenitor cell reduction and dysfunction in salt-sensitive hypertension.
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内皮素 1 激活内皮素 A 受体/NADPH 氧化酶途径和减少的抗氧化剂对盐敏感性高血压中的内皮祖细胞减少和功能障碍有重要影响
DOI：
10.1161/hypertensionaha.111.183368
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Chen AF
中科院分区：
文献类型：
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作者：
Chen DD;Dong YG;Yuan H;Chen AF
高血压患者循环内皮祖细胞（EPCs）减少，与高血压死亡率呈负相关。醋酸脱氧皮质酮(DOCA)-盐性高血压以内皮素（ET） 1升高和氧化应激为特征。我们验证了ET-1通过ETA/NADPH氧化酶途径在盐敏感性高血压中通过升高氧化应激诱导EPC功能障碍的假设。ETA和ETB受体在doca盐大鼠EPCs中均有表达，但只有ETA受体在doca盐大鼠EPCs中显著升高。与假对照组相比，doca盐大鼠的EPC数量和功能减少，并且通过体内阻断ETA受体或NADPH氧化酶可以逆转这两种情况。dopa盐大鼠EPCs中NAPDH氧化酶及其亚基gp91phox、p22phox和Rac1的酶活性增强，同时抗氧化酶锰超氧化物歧化酶、铜锌超氧化物歧化酶和谷胱甘肽过氧化物酶1活性降低。DOCA-salt大鼠EPCs中活性氧水平升高，EPCs端粒酶失活、衰老和凋亡增加，ETA或NADPH氧化酶阻断可挽救EPCs。细胞治疗正常或处理的DOCA EPCs，而不治疗的DOCA EPCs，显著增加DOCA盐大鼠缺血后肢毛细血管密度和血液灌注。doca盐大鼠EPCs中p53和Bax/Bcl-2比值升高，ETA拮抗剂、NADPH氧化酶抑制剂或聚乙二醇超氧化物歧化酶可逆转这一变化。最后，etb缺陷大鼠血浆ET-1升高，EPC数量和端粒酶活性降低。这些结果首次表明，ETA/NADPH氧化酶途径的ET-1激活和抗氧化剂的减少通过增加盐敏感性高血压患者的氧化应激而导致EPC减少和功能障碍。
Circulating endothelial progenitor cells (EPCs) are reduced in hypertension, which inversely correlates with its mortality. Deoxycorticosterone acetate (DOCA)-salt hypertension features elevated endothelin (ET) 1 and oxidative stress. We tested the hypothesis that ET-1 induces EPC dysfunction by elevating oxidative stress through the ETA/NADPH oxidase pathway in salt-sensitive hypertension. Both ETA and ETB receptors were expressed in EPCs, but only ETA receptors were significantly increased in EPCs of DOCA-salt rats. EPC number and function were reduced in DOCA-salt rats compared with sham controls, and both were reversed by in vivo blockade of ETA receptors or NADPH oxidase. The enzymatic activities of NAPDH oxidase and its subunits gp91phox, p22phox, and Rac1 were augmented in EPCs of DOCA-salt rats, with concomitantly decreased antioxidant enzymes manganese superoxide dismutase, copper-zinc superoxide dismutase, and glutathione peroxidase 1. Reactive oxygen species level was elevated in EPCs from DOCA-salt rats, accompanied by increased EPC telomerase inactivation, senescence, and apoptosis, which were rescued by ETA or NADPH oxidase blockade. Cell therapy of normal or treated DOCA EPCs, but not untreated DOCA EPCs, significantly increased capillary density and blood perfusion in ischemic hindlimbs of DOCA-salt rats. p53 and Bax/Bcl-2 ratios were increased in EPCs of DOCA-salt rats, which were reversed by ETA antagonist, NADPH oxidase inhibitor, or polyethylene glycol-superoxide dismutase. Finally, in ETB-deficient rats, plasma ET-1 was elevated, and EPC number and telomerase activity were diminished. These results demonstrate, for the first time, that both ET-1 activation of ETA/NADPH oxidase pathway and diminished antioxidants critically contribute to EPC reduction and dysfunction via increased oxidative stress in salt-sensitive hypertension.