Sawle P, Foresti R, Green C J, Motterlini R
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.
FEBS Lett. 2001 Nov 23;508(3):403-6. doi: 10.1016/s0014-5793(01)03117-9.
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.
同型半胱氨酸（Hcy）代谢紊乱会导致高同型半胱氨酸血症，这种病症与一氧化氮（NO）生物利用度受损、组织缺氧以及血管疾病风险增加有关。在此，我们研究了Hcy如何调节血管内皮细胞中由NO释放剂和缺氧诱发的应激蛋白血红素加氧酶-1（HO-1）的诱导作用。我们发现，Hcy（0.5 mM）显著降低了硝普钠（SNP，0.5 mM）诱导的血红素加氧酶活性增加和HO-1蛋白表达，但不影响S-亚硝基-N-乙酰青霉胺介导的HO-1激活。先用Hcy预处理细胞，然后加入含SNP的新鲜培养基，细胞仍表现出血红素加氧酶活性增强。有趣的是，高水平的Hcy也能够以浓度依赖的方式消除缺氧介导的HO-1表达。这些新发现表明，高同型半胱氨酸血症会干扰细胞应对和适应应激条件所需的关键信号通路。
