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Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells
Tuanjie Chang1, Rui Wang, Lingyun Wu
1Department of Pharmacology, College of Medicine, and The Cardiovascular Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Abstract:
Methylglyoxal (MG) is a metabolite of glucose. Our previous study demonstrated an elevated MG level with an increased oxidative stress in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. Whether MG causes the generation of nitric oxide (NO) and superoxide anion (O2*-), leading to peroxynitrite (ONOO-) formation in VSMCs, was investigated in the present study. Cultured rat thoracic aortic SMCs (A-10) were treated with MG or other different agents. Oxidized DCF, reflecting H2O2 and ONOO- production, was significantly increased in a concentration- and time-dependent manner after the treatment of SMCs with MG (3-300 microM) for 45 min-18 h (n = 12). MG-increased oxidized DCF was effectively blocked by reduced glutathione or N-acetyl-l-cysteine, as well as L-NAME (p < 0.05, n = 12). Both O2*- scavenger SOD and NAD(P)H oxidase inhibitor DPI significantly decreased MG-induced oxidized DCF formation. MG significantly and concentration-dependently increased NO and O2*- generation in A-10 cells, which was significantly inhibited by L-NAME and SOD or DPI, respectively. In conclusion, MG induces significant generation of NO and O2*- in rat VSMCs, which in turn causes ONOO- formation. An elevated MG level and the consequential ROS/RNS generation would alter cellular signaling pathways, contributing to the development of different insulin resistance states such as diabetes or hypertension.
Insights
Methylglyoxal (MG) increases nitric oxide (NO) and superoxide anion (O2*-) in vascular smooth muscle cells, leading to peroxynitrite (ONOO-) formation. This contributes to insulin resistance in conditions like diabetes and hypertension.
Area of Science:
- Biochemistry
- Cell Biology
- Cardiovascular Research
Background:
- Methylglyoxal (MG), a glucose metabolite, is linked to oxidative stress in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats.
- Elevated MG levels are implicated in cellular dysfunction and disease pathogenesis.
Purpose of the Study:
- To investigate if MG induces nitric oxide (NO) and superoxide anion (O2*-) generation in VSMCs.
- To determine if this generation leads to peroxynitrite (ONOO-) formation.
- To explore the role of MG in cellular signaling relevant to insulin resistance.
Main Methods:
- Cultured rat thoracic aortic SMCs (A-10) were treated with varying concentrations of MG.
- Oxidative stress markers, including H2O2 and ONOO- production (measured by oxidized DCF), were assessed.
- The roles of NO, O2*-, reduced glutathione, N-acetyl-l-cysteine, L-NAME, SOD, and DPI were investigated.
Main Results:
- MG significantly increased oxidized DCF in a concentration- and time-dependent manner.
- MG treatment elevated NO and O2*- generation in A-10 cells.
- These effects were attenuated by antioxidants (reduced glutathione, N-acetyl-l-cysteine) and inhibitors (L-NAME, SOD, DPI).
Conclusions:
- MG induces significant NO and O2*- generation in rat VSMCs.
- This generation leads to peroxynitrite (ONOO-) formation.
- Elevated MG and subsequent reactive oxygen/nitrogen species (ROS/RNS) generation may contribute to insulin resistance states like diabetes and hypertension.
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