Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation.
Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation.
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DOI：
10.1111/acel.12204
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发表时间：
2014-06
期刊：
影响因子：
7.8
通讯作者：
Nangaku M
中科院分区：
文献类型：
--
作者：
Jo-Watanabe A;Ohse T;Nishimatsu H;Takahashi M;Ikeda Y;Wada T;Shirakawa J;Nagai R;Miyata T;Nagano T;Hirata Y;Inagi R;Nangaku M
内皮功能障碍是心血管疾病(CVD)的一个主要因素，尤其是在老年人中。研究表明糖基化在非生理学模型中的内皮功能障碍中的作用，但糖基化在年龄相关的内皮功能障碍中的生理学作用一直没有得到很好的解决。在这里，为了研究血管糖基化如何影响与年龄相关的内皮功能，我们使用了系统性高表达乙草酸酶I(GLO1)的大鼠，该酶能解毒糖基化的代表性前体甲基乙二醛(MG)。实验分为青年(13周龄)、中年(53周龄)野生型和GLO1转基因(WT/GLO1TG)三组。GLO1TG大鼠的糖化加速与年龄相关，并伴有较低的主动脉羧甲基赖氨酸(CML)和尿8-羟基脱氧鸟苷(8-OHdG)水平。GLO1TG大鼠的增龄性内皮依赖性血管松弛功能受损程度减轻，而WT和GLO1TG大鼠的非内皮依赖性血管松弛功能无明显差异。中年WT大鼠一氧化氮(NO)生成减少，而GLO1TG中年大鼠则无明显变化。内皮型一氧化氮合酶(ENOS)在Thr495上的磷酸化和Ser1177上的去磷酸化导致的内皮型一氧化氮合酶(ENOS)的年龄相关性失活在GLO1TG大鼠中得到改善。在体外，MG增加原代培养的人主动脉内皮细胞(HAECs)eNOS的磷酸化(Thr495)，过表达GLO1可降低糖化应激和eNOS的磷酸化(Thr495)。总而言之，GLO1减少了与年龄相关的内皮细胞的糖化和氧化应激，改变了eNOS的磷酸化，并减轻了内皮功能障碍。作为一种分子机制，GLO1通过减少糖化应激来减轻eNOS(Thr495)的抑制磷酸化。我们的研究表明，钝化的糖化应激可防止血管内皮功能障碍对血管老化的长期影响。
Endothelial dysfunction is a major contributor to cardiovascular disease (CVD), particularly in elderly people. Studies have demonstrated the role of glycation in endothelial dysfunction in nonphysiological models, but the physiological role of glycation in age-related endothelial dysfunction has been poorly addressed. Here, to investigate how vascular glycation affects age-related endothelial function, we employed rats systemically overexpressing glyoxalase I (GLO1), which detoxifies methylglyoxal (MG), a representative precursor of glycation. Four groups of rats were examined, namely young (13 weeks old), mid-age (53 weeks old) wild-type, and GLO1 transgenic (WT/GLO1 Tg) rats. Age-related acceleration in glycation was attenuated in GLO1 Tg rats, together with lower aortic carboxymethyllysine (CML) and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Age-related impairment of endothelium-dependent vasorelaxation was attenuated in GLO1 Tg rats, whereas endothelium-independent vasorelaxation was not different between WT and GLO1 Tg rats. Nitric oxide (NO) production was decreased in mid-age WT rats, but not in mid-age GLO1 Tg rats. Age-related inactivation of endothelial NO synthase (eNOS) due to phosphorylation of eNOS on Thr495 and dephosphorylation on Ser1177 was ameliorated in GLO1 Tg rats. In vitro, MG increased phosphorylation of eNOS (Thr495) in primary human aortic endothelial cells (HAECs), and overexpression of GLO1 decreased glycative stress and phosphorylation of eNOS (Thr495). Together, GLO1 reduced age-related endothelial glycative and oxidative stress, altered phohphorylation of eNOS, and attenuated endothelial dysfunction. As a molecular mechanism, GLO1 lessened inhibitory phosphorylation of eNOS (Thr495) by reducing glycative stress. Our study demonstrates that blunting glycative stress prevents the long-term impact of endothelial dysfunction on vascular aging.
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DOI：
10.1152/ajprenal.90575.2008
发表时间：
2009-04-01
影响因子：
4.2
作者：
Kumagai, Takanori;Nangaku, Masaomi;Inagi, Reiko
通讯作者：
Inagi, Reiko
吡哆醇通过 PKCa 信号通路抑制人脐静脉内皮细胞氧化低密度脂蛋白诱导的内皮 NOS 解偶联
影响因子：
7.3
作者：
Xie, Liping;Liu, Zhen;Ji, Yong
通讯作者：
Ji, Yong
影响因子：
7.7
作者：
Freidja ML;Tarhouni K;Toutain B;Fassot C;Loufrani L;Henrion D
通讯作者：
Henrion D
DOI：
10.1042/cs20100476
发表时间：
2011-05
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Seals DR;Jablonski KL;Donato AJ
通讯作者：
Donato AJ
影响因子：
37.8
作者：
Lakatta, EG;Levy, D
通讯作者：
Levy, D