Glyoxalase I reduces glycative and oxidative stress and prevents age‐related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation. Issue 3 (24th February 2014)

• Record Type: Journal Article
• Authors: Jo‐Watanabe, Airi; Ohse, Takamoto; Nishimatsu, Hiroaki; Takahashi, Masao; Ikeda, Yoichiro; Wada, Takehiko; Shirakawa, Jun‐ichi; Nagai, Ryoji; Miyata, Toshio; Nagano, Tetsuo; Hirata, Yasunobu; Inagi, Reiko; Nangaku, Masaomi
• Is Part Of: Aging cell. Volume 13:Issue 3(2014:Jun.)
• Page Start: 519
• Page End: 528
• Publication Date: 2014-02-24
• Subjects: Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12204
• Languages: English
• ISSNs: 1474-9718

Abstract

<abstract abstract-type="main" id="acel12204-abs-0001"> <title>Summary</title> <p>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 <italic>glyoxalase I</italic> (<italic>GLO1</italic>), 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 <italic>GLO1</italic> transgenic (WT/<italic>GLO1</italic> Tg) rats. Age‐related acceleration in glycation was attenuated in <italic>GLO1</italic> 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 <italic>GLO1</italic> Tg rats, whereas endothelium‐independent vasorelaxation was not different between WT and <italic>GLO1</italic> Tg rats. Nitric oxide (NO) production was decreased in mid‐age WT rats, but not in mid‐age <italic>GLO1</italic> Tg rats. Age‐related inactivation of endothelial NO synthase (eNOS) due to phosphorylation of eNOS on Thr495 and dephosphorylation on Ser1177 was ameliorated in <italic>GLO1</italic> Tg rats. <italic>In vitro</italic>, 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.</p> </abstract>