Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function
Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function
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DOI：
10.1073/pnas.1113319109
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发表时间：
2012-03-13
影响因子：
11.1
通讯作者：
Hare, Joshua M.
中科院分区：
文献类型：
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作者：
Beigi, Farideh;Gonzalez, Daniel R.;Hare, Joshua M.
尽管蛋白质 S-亚硝基化越来越多地被认为介导一氧化氮 (NO) 信号传导，但蛋白质去亚硝基化在生理学中的作用仍然未知。在这里，我们发现 S-亚硝基谷胱甘肽还原酶 (GSNOR) 是一种通过促进蛋白质去亚硝基化来控制 S-亚硝基化水平的酶，可调节外周血管张力和 β-肾上腺素能激动剂刺激的心肌收缩力，以前仅将其归因于 NO/cGMP。 GSNOR 缺陷小鼠表现出外周血管张力降低和 β 肾上腺素能正性肌力反应抑制，这与 β 激动剂诱导的心脏兰尼碱受体 2 (RyR2) 去亚硝基化受损有关，导致钙渗漏。这些结果表明，无论是在基础条件下还是在肾上腺素能激活后，全身血流动力学反应（血管张力和心肌收缩力）都是通过NO合酶/GSNOR的协同作用来调节的，并且异常的去亚硝基化会损害心血管功能。我们的研究结果支持动态 S-亚硝基化/去亚硝基化反应对于心血管调节至关重要的观点。
Although protein S-nitrosylation is increasingly recognized as mediating nitric oxide (NO) signaling, roles for protein denitrosylation in physiology remain unknown. Here, we show that S-nitrosoglutathione reductase (GSNOR), an enzyme that governs levels of S-nitrosylation by promoting protein denitrosylation, regulates both peripheral vascular tone and beta-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed beta-adrenergic inotropic responses that were associated with impaired beta-agonist-induced denitrosylation of cardiac ryanodine receptor 2 (RyR2), resulting in calcium leak. These results indicate that systemic hemodynamic responses (vascular tone and cardiac contractility), both under basal conditions and after adrenergic activation, are regulated through concerted actions of NO synthase/GSNOR and that aberrant denitrosylation impairs cardiovascular function. Our findings support the notion that dynamic S-nitrosylation/denitrosylation reactions are essential in cardiovascular regulation.