GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation.
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation.
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GSNOR 通过将 Akt S-亚硝基化转变为磷酸化来调节高同型半胱氨酸血症诱导的 T 细胞活化和动脉粥样硬化。
DOI：
10.1016/j.redox.2018.04.021
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发表时间：
2018-07
期刊：
影响因子：
11.4
通讯作者：
Feng J
中科院分区：
文献类型：
--
作者：
Li J;Zhang Y;Zhang Y;Lü S;Miao Y;Yang J;Huang S;Ma X;Han L;Deng J;Fan F;Liu B;Huo Y;Xu Q;Chen C;Wang X;Feng J
适应性免疫系统在高同型半胱氨酸血症(HHcy)加速的动脉粥样硬化中起关键作用。最近的研究表明，HHcy通过增加氧化应激和降低血管中氧化还原敏感蛋白残基的S亚硝化水平来加重动脉粥样硬化。然而，S-亚硝化是否以及如何促进T细胞驱动的动脉粥样硬化仍不清楚。在本研究中，我们报道了同型半胱氨酸通过诱导S亚硝基谷胱甘肽还原酶(GSNOR)来降低T细胞中蛋白质S亚硝化的水平，S亚硝基谷胱甘肽还原酶是催化S亚硝基谷胱甘肽的关键脱氮酶，而S亚硝基谷胱甘肽是一氧化氮在体内的主要恢复形式。因此，炎性细胞因子[干扰素-γ(干扰素-γ)和白介素2]的分泌和T细胞的增殖增加。GSNOR基因敲除或GSNO刺激可纠正HHcy诱导的炎性细胞因子分泌和T细胞增殖。对Akt基因Cys224的定点突变研究表明，该位点的S亚硝化是导致Akt Ser473蛋白磷酸化水平降低的关键因素，从而导致Akt信号转导功能受损。此外，在HHcy攻击中，与GSNOR+/+ApoE-/-对照相比，GSNOR-/-ApoE-/-双基因敲除小鼠表现出T细胞活化减少，同时动脉粥样硬化减轻。过继将GSNOR-/-T细胞转移到喂饲同型半胱氨酸(Hcy)的ApoE-/-小鼠可减轻动脉粥样硬化，斑块中浸润的T细胞和巨噬细胞较少。冠心病患者血浆同型半胱氨酸水平与外周血单个核细胞和干扰素-γ+T细胞GSNOR表达呈正相关，与T细胞S-亚硝化水平呈负相关。这些数据表明，在HHcy诱导的动脉粥样硬化过程中，T细胞被激活，部分是通过GSNOR依赖的Akt反硝化作用。因此，抑制T细胞中的GSNOR可能会降低动脉粥样硬化的风险。同型半胱氨酸通过上调T细胞GSNOR表达减少S亚硝化反应。同型半胱氨酸诱导的GSNOR在T细胞激活过程中将SNO-Akt转换为p-Akt。Akt在Cys224位的S亚硝化可抑制其在Ser473位的磷酸化。清除T细胞中的GSNOR可改善HHcy诱导的体内动脉粥样硬化。
The adaptive immune system plays a critical role in hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Recent studies suggest that HHcy aggravates atherosclerosis with elevated oxidative stress and reduced S-nitrosylation level of redox-sensitive protein residues in the vasculature. However, whether and how S-nitrosylation contributes to T-cell-driven atherosclerosis remain unclear. In the present study, we report that HHcy reduced the level of protein S-nitrosylation in T cells by inducing S-nitrosoglutathione reductase (GSNOR), the key denitrosylase that catalyzes S-nitrosoglutathione (GSNO), which is the main restored form of nitric oxide in vivo. Consequently, secretion of inflammatory cytokines [interferon-γ (IFN-γ) and interleukin-2] and proliferation of T cells were increased. GSNOR knockout or GSNO stimulation rectified HHcy-induced inflammatory cytokine secretion and T-cell proliferation. Site-directed mutagenesis of Akt at Cys224 revealed that S-nitrosylation at this site was pivotal for the reduced phosphorylation at Akt Ser473, which led to impaired Akt signaling. Furthermore, on HHcy challenge, as compared with GSNOR+/+ApoE-/- littermate controls, GSNOR-/-ApoE-/- double knockout mice showed reduced T-cell activation with concurrent reduction of atherosclerosis. Adoptive transfer of GSNOR-/- T cells to ApoE-/- mice fed homocysteine (Hcy) decreased atherosclerosis, with fewer infiltrated T cells and macrophages in plaques. In patients with HHcy and coronary artery disease, the level of plasma Hcy was positively correlated with Gsnor expression in peripheral blood mononuclear cells and IFN-γ+ T cells but inversely correlated with the S-nitrosylation level in T cells. These data reveal that T cells are activated, in part via GSNOR-dependent Akt denitrosylation during HHcy-induced atherosclerosis. Thus, suppression of GSNOR in T cells may reduce the risk of atherosclerosis. HHcy decreases S-nitrosylation by upregulating GSNOR expression in T cells. HHcy-induced GSNOR switches SNO-Akt to p-Akt during T-cell activation. S-nitrosylation ofAkt at Cys224 inhibits its phosphorylation at Ser473. GSNOR ablation in T cells ameliorates HHcy-induced atherosclerosis in vivo.
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