Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent β1-subunit glutathionylation: implications for angiotensin II-induced vascular dysfunction.
Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent β1-subunit glutathionylation: implications for angiotensin II-induced vascular dysfunction.
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通过 NADPH 氧化酶依赖性 β1 亚基谷胱甘肽氧化抑制血管 Na -K 泵：对血管紧张素 II 诱导的血管功能障碍的影响。
DOI：
10.1016/j.freeradbiomed.2013.06.040
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发表时间：
2013
影响因子：
7.4
通讯作者：
Figtree,GemmaA
中科院分区：
文献类型：
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作者：
Liu,Chia-Chi;KarimiGalougahi,Keyvan;Weisbrod,RobertM;Hansen,Thomas;Ravaie,Ramtin;Nunez,Andrea;Liu,YiB;Fry,Natasha;Garcia,Alvaro;Hamilton,ElishaJ;Sweadner,KathleenJ;Cohen,RichardA;Figtree,GemmaA
Na+-K+泵β1亚基的谷胱甘肽化是心肌细胞生理和病理生理泵抑制的关键分子机制。其对其他组织中Na+-K+泵调节的贡献尚不清楚，并且鉴于对特定β亚基亚型表达和受体偶联途径的依赖性，无法假定其对其他组织中Na+-K+泵调节的贡献。由于Na+-K+泵活性是通过影响[Ca 2 +]i来调节血管紧张度的重要决定因素，我们研究了Na+-K+泵的氧化调节在介导血管紧张素II（Ang II）诱导的血管反应性增加中的作用。β1-亚单位谷胱甘肽加合物在基线时存在，并在兔主动脉环、原代兔主动脉血管平滑肌细胞（VSMCs）和人动脉节段中暴露于Ang II后增加。在VSMC中，Ang II诱导的谷胱甘肽化与Na+-K+ ATP酶活性的显著降低相关，NADPH氧化酶抑制肽tat-gp 91 ds可消除这种效应。在主动脉段，Ang II诱导的谷胱甘肽化与K+诱导的血管舒张减少相关，这是一个经验证的泵活性指数。血管紧张素II诱导的Na+-K+ ATP酶的氧化抑制和K+诱导的舒张作用的降低可通过与重组FXYD 3蛋白预孵育来逆转，该蛋白已知可促进β1亚基的去谷胱甘肽化。敲除FXYD 1显著降低了小鼠模型中K+诱导的舒张。卡托普利（8 mg/kg/d，连续7天）减弱血管紧张素Ⅱ（Ang Ⅱ）信号通路，降低兔主动脉中膜超氧化物歧化酶（DHE）水平，降低β1亚单位谷胱甘肽化，增强K+诱导的血管舒张作用。血管紧张素II通过NADPH氧化酶依赖性的β1亚基谷胱甘肽化抑制VSMC中的Na+-K+泵，这一新发现的信号通路可能有助于改变血管张力。FXYD蛋白减少Na+-K+泵的氧化抑制，并可能在氧化应激条件下对血管系统具有重要的保护作用。
Glutathionylation of the Na+-K+pump’s β1-subunit is a key molecular mechanism of physiological and pathophysiological pump inhibition in cardiac myocytes. Its contribution to Na+-K+pump regulation in other tissues is unknown, and cannot be assumed given the dependence on specific β-subunit isoform expression and receptor-coupled pathways. As Na+-K+pump activity is an important determinant of vascular tone through effects on [Ca2+]i, we have examined the role of oxidative regulation of the Na+-K+pump in mediating angiotensin II (Ang II)-induced increases in vascular reactivity. β1-subunit glutathione adducts were present at baseline and increased by exposure to Ang II in rabbit aortic rings, primary rabbit aortic vascular smooth muscle cells (VSMCs), and human arterial segments. In VSMCs, Ang II-induced glutathionylation was associated with marked reduction in Na+-K+ATPase activity, an effect that was abolished by the NADPH oxidase inhibitory peptide, tat-gp91ds. In aortic segments, Ang II-induced glutathionylation was associated with decreased K+-induced vasorelaxation, a validated index of pump activity. Ang II-induced oxidative inhibition of Na+-K+ATPase and decrease in K+-induced relaxation were reversed by preincubation of VSMCs and rings with recombinant FXYD3 protein that is known to facilitate deglutathionylation of β1-subunit. Knock-out of FXYD1 dramatically decreased K+-induced relaxation in a mouse model. Attenuation of Ang II signalingin vivoby captopril (8 mg/kg/day for 7 days) decreased superoxide-sensitive DHE levels in the media of rabbit aorta, decreased β1-subunit glutathionylation, and enhanced K+-induced vasorelaxation. Ang II inhibits the Na+-K+pump in VSMCs via NADPH oxidase-dependent glutathionylation of the pump’s β1-subunit, and this newly identified signaling pathway may contribute to altered vascular tone. FXYD proteins reduce oxidative inhibition of the Na+-K+pump and may have an important protective role in the vasculature under conditions of oxidative stress.