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Long-term methylglyoxal treatment causes endothelial dysfunction of rat isolated mesenteric artery
Masashi Mukohda1, Tomoka Morita, Muneyoshi Okada
1Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
Abstract:
Methylglyoxal (MGO) is a metabolite of glucose and likely related to pathogenesis of diabetes-related vascular complications including hypertension. In this study, long-term effects of MGO on endothelial function were examined. Rat isolated mesenteric artery was treated for 3 days with MGO using an organ culture method. The contractility, morphology and protein expression of organ-cultured artery were examined. MGO (42 µM, 3 days) impaired acetylcholine (ACh: 1 nM-300 µM)-induced endothelium-dependent relaxation, while it had no effect on sodium nitroprusside (0.1 nM-10 µM)-induced endothelium-independent relaxation. MGO decreased ACh (3 µM)-induced nitric oxide (NO) production as measured by a fluorescence NO indicator, diaminofluorescein-2. Consistently, MGO inhibited ACh (3 µM)-induced phosphorylation of vasodilator stimulated phosphoprotein (an indicator of cyclic GMP production). MGO induced apoptosis in endothelium as detected by TdT-mediated dUTP-biotin nick-end labeling staining. MGO induced accumulation of superoxide in endothelium as detected by dihydroethidium staining. MGO decreased protein expression of endothelial NO synthase (eNOS). Gp91ds-tat (0.1 µM), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), prevented the impairment of endothelium-dependent relaxation and the decrease in eNOS protein caused by MGO. The present results demonstrated that long-term MGO treatment impairs endothelium-dependent relaxation through NOX-derived increased superoxide-mediated endothelial apoptosis.
Insights
Long-term methylglyoxal (MGO) exposure damages blood vessel lining by increasing oxidative stress and cell death. This impairs blood vessel relaxation, contributing to hypertension and diabetes complications.
Area of Science:
- Vascular Biology
- Metabolic Disorders
- Oxidative Stress
Background:
- Methylglyoxal (MGO), a glucose metabolite, is implicated in diabetic vascular complications like hypertension.
- Understanding MGO's long-term impact on endothelial function is crucial for disease pathogenesis research.
Purpose of the Study:
- To investigate the chronic effects of methylglyoxal (MGO) on rat mesenteric artery endothelial function, morphology, and protein expression.
Main Methods:
- Organ culture of rat mesenteric arteries with MGO for 3 days.
- Assessment of endothelium-dependent and -independent relaxation.
- Measurement of nitric oxide (NO) production, cyclic GMP levels, apoptosis, and superoxide accumulation.
- Analysis of endothelial NO synthase (eNOS) protein expression.
- Evaluation of NADPH oxidase (NOX) inhibition using Gp91ds-tat.
Main Results:
- MGO significantly impaired acetylcholine-induced endothelium-dependent relaxation but not sodium nitroprusside-induced relaxation.
- MGO reduced nitric oxide (NO) production and cyclic GMP signaling.
- MGO induced endothelial apoptosis and increased superoxide levels.
- MGO decreased eNOS protein expression, an effect reversed by NOX inhibition.
Conclusions:
- Long-term MGO exposure impairs endothelial function primarily through NOX-derived superoxide-mediated endothelial apoptosis.
- This mechanism highlights MGO's role in the pathogenesis of diabetes-related vascular complications.
