Increased Methylglyoxal and Oxidative Stress in Hypertensive Rat Vascular Smooth Muscle Cells

Abstract

Abstract-Methylglyoxal can yield advanced glycation end products via nonenzymatic glycation of proteins. Whether methylglyoxal contributes to the pathogenesis of hypertension has not been clear. The aim of the present study was to investigate whether the levels of methylglyoxal and methylglyoxal-induced advanced glycation end products were enhanced and whether methylglyoxal increased oxidative stress, activated nuclear factor-B (NF-B), and increased intracellular adhesion molecule-1 (ICAM-1) content in vascular smooth muscle cells from spontaneously hypertensive rats. Basal cellular levels of methylglyoxal and advanced glycation end products were more than 2-fold higher (PϽ0.05) in cells from hypertensive rats than from normotensive Wistar-Kyoto rats. This correlated with levels of oxidative stress and oxidized glutathione that were significantly higher in cells from hypertensive rats, whereas levels of glutathione and activities of glutathione reductase and glutathione peroxidase were significantly lower. Basal levels of nuclearly localized NF-B p65 and ICAM-1 protein expression were higher in cells from hypertensive rats than from normotensive rats. Addition of exogenous methylglyoxal to the cultures induced a greater increase in oxidative stress and advanced glycation end products in cells from hypertensive rats compared with normotensive rats and significantly decreased the activities of glutathione reductase and glutathione peroxidase in cells of both rat strains. Methylglyoxal activated NF-B p65 and increased ICAM-1 expression in hypertensive cells, which was inhibited by N-acetylcysteine. Our study demonstrates an elevated methylglyoxal level and advanced glycation end products in cells from hypertensive rats, and methylglyoxal increases oxidative stress, activates NF-B, and enhances ICAM-1 expression. Our findings suggest that that elevated methylglyoxal and associated oxidative stress possibly contribute to the pathogenesis of hypertension. (Hypertension. 2002;39:809-814.)

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

“…AGEs were shown to accumulate also in ageing [8,9] and age-related conditions such as central obesity, dyslipidaemia and hypertension [10][11][12], clustering with impaired glucose metabolism in the setting of metabolic syndrome and associated with systemic inflammation and increased risk of renal and cardiovascular disease [13,14]. Increased amounts of AGEs are formed under these conditions due to several mechanisms, including enhanced carbohydrate and/or lipid substrate availability, increased oxidative and nonoxidative metabolism, impaired detoxification caused by consumption of cofactors of detoxifying enzymes and, in the case of associated renal failure, reduced kidney clearance [15].…”

Lipid Peroxidation Is Not Increased in Patients With Untreated Mild-to-Moderate Hypertension

“…Many animal experiments or in vitro studies in humans support the hypothesis that increased oxidative stress may be one of the initial triggers of vascular remodeling and elevated blood pressure. [1][2][3] In contrast to the huge amount of experimental data available for different species and strains, only few and relatively unconvincing clinical studies support such a hypothesis in the early stages of essential hypertension in humans because of the lack of a reliable clinical biomarker of lipid peroxidation in vivo. 4 Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, and their quantification provides a novel approach to the assessment of oxidative stress in vivo.…”

Pharmacologic approaches against Advanced Glycation End Products (AGEs) in diabetic cardiovascular disease

“…In diabetic rats, MGO-induced modifications of mitochondrial proteins were associated with increased superoxide formation in mitochondria (8). Furthermore, MGO modifies glutathione reductase and glutathione peroxidase, resulting in increased oxidative stress (9). MGO also impairs proteasome function (10) and alters overall cellular function (11).…”