Open AccessG lyoxalase I reduces glycative and oxidative stress and prevents age‐related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation
Author(s) -
JoWatanabe Airi,
Ohse Takamoto,
Nishimatsu Hiroaki,
Takahashi Masao,
Ikeda Yoichiro,
Wada Takehiko,
Shirakawa Junichi,
Nagai Ryoji,
Miyata Toshio,
Nagano Tetsuo,
Hirata Yasunobu,
Inagi Reiko,
Nangaku Masaomi
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12204
Subject(s) - enos , glycation , methylglyoxal , endothelial dysfunction , oxidative stress , medicine , endocrinology , dephosphorylation , endothelium , phosphorylation , nitric oxide synthase type iii , nitric oxide , oxidative phosphorylation , nitric oxide synthase , biology , chemistry , biochemistry , diabetes mellitus , phosphatase , enzyme
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 T g) rats. Age‐related acceleration in glycation was attenuated in GLO1 T g 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 T g rats, whereas endothelium‐independent vasorelaxation was not different between WT and GLO1 T g rats. Nitric oxide ( NO ) production was decreased in mid‐age WT rats, but not in mid‐age GLO1 T g rats. Age‐related inactivation of endothelial NO synthase ( eNOS ) due to phosphorylation of eNOS on T hr495 and dephosphorylation on S er1177 was ameliorated in GLO1 T g rats. In vitro , MG increased phosphorylation of eNOS ( T hr495) in primary human aortic endothelial cells ( HAEC s), and overexpression of GLO 1 decreased glycative stress and phosphorylation of eNOS ( T hr495). Together, GLO 1 reduced age‐related endothelial glycative and oxidative stress, altered phohphorylation of eNOS , and attenuated endothelial dysfunction. As a molecular mechanism, GLO 1 lessened inhibitory phosphorylation of e NOS ( T hr495) by reducing glycative stress. Our study demonstrates that blunting glycative stress prevents the long‐term impact of endothelial dysfunction on vascular aging.