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.
Highlights
Vascular aging is accompanied by endothelial dysfunction, which refers to functional alterations of the normal endothelial phenotype of arteries, represented by impaired endothelium-dependent relaxation (EDR; Lakatta & Levy, 2003; Brandes et al, 2005; Seals et al, 2011)
Endothelial dysfunction is a major contributor to cardiovascular disease (CVD), the leading cause of death, in elderly people (Lloyd-Jones et al, 2010; Seals et al, 2011)
As NO bioavailability is dependent on the balance between its production by endothelial nitric oxide synthase and loss through reaction with superoxide, we investigated the involvement of these factors
Summary
Vascular aging is accompanied by endothelial dysfunction, which refers to functional alterations of the normal endothelial phenotype of arteries, represented by impaired endothelium-dependent relaxation (EDR; Lakatta & Levy, 2003; Brandes et al, 2005; Seals et al, 2011). Endothelial dysfunction is a major contributor to cardiovascular disease (CVD), the leading cause of death, in elderly people (Lloyd-Jones et al, 2010; Seals et al, 2011). Glycation is a nonenzymatic chemical reaction between an amino group of proteins or nucleotides and a reducing sugar which leads to the formation of irreversible end-products (advanced glycation end-products: AGEs). Methylglyoxal (MG) is a representative AGE precursor which is derived from glycolysis or glucose degradation and reacts with protein, nucleotides and basic phospholipids (Thornalley, 2008). Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd
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