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

Aging Cell

Airi Jo-Watanabe¹  Takamoto Ohse¹  Hiroaki Nishimatsu⁶  Masao Takahashi²  Yoichiro Ikeda¹  Takehiko Wada¹  Jun-ichi Shirakawa⁵  Ryoji Nagai⁵  Toshio Miyata³  Tetsuo Nagano⁷  Yasunobu Hirata⁴  Reiko Inagi¹ 

[1] Division of Nephrology and Endocrinology, Tokyo, Japan;Department of Cardiovascular Medicine, the University of Tokyo, Graduate School of Medicine, Tokyo, Japan;Graduate School of Medicine, Tohoku University, Miyagi, Japan;Department of Advanced Clinical Science and Therapeutics;Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, Kumamoto, Japan;Department of Urology, the University of Tokyo, Tokyo, Japan;Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan

关键词: advanced glycation end‐products;    aging;    endothelial dysfunction;    endothelial nitric oxide synthase;    glycation;    glyoxalase I;   

DOI  :  10.1111/acel.12204

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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