title: Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation.
abstract: 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.
authors.affiliation: Division of Nephrology and Endocrinology, Tokyo, Japan.
authors.forename: Airi
authors.initials: A
authors.lastname: Jo-Watanabe
authors.forename: Takamoto
authors.initials: T
authors.lastname: Ohse
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Masao
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Takehiko
authors.initials: T
authors.lastname: Wada
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Shirakawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagai
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000367:Age Factors; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D055647:Rats, Transgenic; D014162:Transfection
chemical_list: D017127:Glycation End Products, Advanced; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: advanced glycation end-products; aging; endothelial dysfunction; endothelial nitric oxide synthase; glycation; glyoxalase I