Homocysteine attenuates endothelial haem oxygenase-1 induction by nitric oxide (NO) and hypoxia

The disrupted metabolism of homocysteine (Hcy) causes hyperhomocysteinemia, a condition associated with the impairment of nitric oxide (NO) bio-availability, tissue hypoxia and increased risk of vascular disease. Here, we examined how Hey modulates the induction of the stress protein haem oxygenase-1 (HO-1) evoked by NO releasing agents and hypoxia in vascular endothelial cells. We found that Hey (0.5 mM) markedly reduced the increase in haem oxygenase activity and HO-1 protein expression induced by sodium nitroprusside (SNP, 0.5 mM) but did not affect HO-1 activation mediated by S-nitroso-N-acetyl-penicillamine. Cells pre-treated with Hey followed by addition of fresh medium containing SNP still exhibited an augmented haem oxygenase activity. Interestingly, high levels of Hey were also able to abolish hypoxia-mediated HO-1 expression in a concentration-dependent manner. These novel findings indicate that hyperhomocysteinemia interferes with crucial signaling pathways required by cells to respond and adapt to stressful conditions. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.