Journal Article

Homocysteine-Induced Endothelin-1 Release Is Dependent on Hyperglycaemia and Reactive Oxygen Species Production in Bovine Aortic Endothelial Cells

Lees, Delphine M., Sethi, Amarjit S., Corder, Roger, Douthwaite, Julie A., Dawnay, Anne B.

2006

Overview

Background: Elevated plasma homocysteine (Hcy) is a risk factor for coronary disease. The objective of this study was to investigate whether Hcy either alone or in high glucose conditions induces endothelin-1 (ET-1) synthesis via the production of reactive oxygen species (ROS). Methods: Bovine aortic endothelial cells were grown in high (25 mmol/l) and low (5 mmol/l) glucose medium. Results: In high glucose, Hcy caused a time-dependent increase in ET-1 release, which was greatest with 50 µmol/l Hcy at 24 h (p < 0.01). This effect was not seen in low glucose conditions. In high glucose and 50 µmol/l Hcy, ET-1 mRNA levels were maximal after 1 h (p < 0.05). Tissue factor mRNA levels were raised at 4 h (p < 0.05) and functional activity was raised at 6 h (p < 0.01). Intracellular ROS production was increased by 50 µmol/l Hcy after 24 h (p < 0.05) but only in high glucose. To investigate the role of mitochondrial metabolism in ROS production, cells were incubated with thenoyltrifluoroacetone (inhibitor of complex II) or carbonyl cyanide m-chlorophenylhydrazone (uncoupler of oxidative phosphorylation). Both compounds abolished the Hcy-induced increase in ROS production and ET-1 release. There was an alteration in intracellular glutathione (GSH) levels with Hcy treatment with more oxidised GSH present. Conclusion: The combined metabolic burden of Hcy and high glucose stimulates ET-1 synthesis in bovine aortic endothelial cells via a mechanism dependent on the production of mitochondrial ROS, but may not be generalisable to all types of endothelial cells.

• Publisher: Karger,S. Karger AG
• Subject: Animals / Aorta - cytology / Biological and medical sciences / Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology / Cattle / Cells, Cultured / Electron Transport Complex II - antagonists & inhibitors / Endothelin-1 - secretion / Endothelium, Vascular - cytology / Endothelium, Vascular - metabolism / Fundamental and applied biological sciences. Psychology / Glucose - administration & dosage / Glutathione - metabolism / Homocysteine - pharmacology / Hyperglycemia - physiopathology / Oxidative Stress - physiology / Reactive Oxygen Species - metabolism / Research Paper / Thenoyltrifluoroacetone - pharmacology / Thromboplastin - metabolism / Uncoupling Agents - pharmacology / Vertebrates: cardiovascular system