Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation

被引：56

作者：

Jo-Watanabe, Airi ^{[1
]}

Ohse, Takamoto ^{[1
]}

Nishimatsu, Hiroaki ^{[2
]}

Takahashi, Masao ^{[3
]}

Ikeda, Yoichiro ^{[1
]}

Wada, Takehiko ^{[1
]}

Shirakawa, Jun-ichi ^{[4
]}

Nagai, Ryoji ^{[4
]}

Miyata, Toshio ^{[5
]}

Nagano, Tetsuo ^{[6
]}

Hirata, Yasunobu ^{[7
]}

Inagi, Reiko ^{[1
,8
]}

Nangaku, Masaomi ^{[1
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Div Nephrol & Endocrinol, Tokyo 1138655, Japan

[2] Univ Tokyo, Dept Urol, Grad Sch Med, Tokyo 1138655, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Tokyo 1138655, Japan

[4] Tokai Univ, Dept Biosci, Sch Agr, Lab Food & Regulat Biol, Kumamoto, Japan

[5] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan

[6] Univ Tokyo, Grad Sch Med, Grad Sch Pharmaceut Sci, Tokyo 1138655, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Adv Clin Sci & Therapeut, Tokyo 1138655, Japan

[8] Univ Tokyo, Grad Sch Med, Tokyo 1138655, Japan

来源：

AGING CELL | 2014年 / 13卷 / 03期

基金：

日本学术振兴会;

关键词：

advanced glycation end-products; aging; endothelial dysfunction; endothelial nitric oxide synthase; glycation; glyoxalase I; DISEASE; RATS; TETRAHYDROBIOPTERIN; METHYLGLYOXAL; ARTERIES; PROTEIN; SYSTEM;

D O I：

10.1111/acel.12204

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：519 / 528

页数：10

共 19 条

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