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 Hcy 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 Hcy (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 Hcy followed by addition of fresh medium containing SNP still exhibited an augmented haem oxygenase activity. Interestingly, high levels of Hcy 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.
Sawle
P
P
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.
Foresti
R
R
Green
C J
CJ
Motterlini
R
R
D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006710:Homocysteine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
D003470:Culture Media; D020030:Nitric Oxide Donors; D006710:Homocysteine; D009599:Nitroprusside; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D006419:Heme Oxygenase (Decyclizing)