加拿大多伦多圣米高医院的研究人员发现一种酶有新的作用,它有可能会保护因为贫血引起的损伤和死亡。
该医院李嘉诚知识研究所研究员格雷戈黑尔说,“发现这一机制有可能为贫血病人带来新的治疗并改善治疗的效果。”
世界四分之一的人以及50%手术病人会有贫血。造成贫血的原因不同,包括感染(疟疾、HIV和寄生虫)、营养不良(铁、叶酸和B12)、遗传变异、怀孕、创伤和手术失血。当血液中红细胞或血红蛋白(从肺和心脏携带氧到身体其它部位的一种富含铁蛋白)数量低于正常就会发生贫血。细胞需要氧来生存和产生所有人体功能所需的能量。
黑尔博士和他的同事们发现,当人体出现贫血时,神经元的一氧化氮合成酶(神经细胞中能产生重要信号分子一氧化氮的酶)会增加人体的反应能力,使人体适应低氧状态并更有效地释放氧到组织。研究人员发现,在贫血的小鼠大脑中一氧化氮合成酶水平会增加,而那些没有这种酶的小鼠会过早死亡。
这项研究发表在美国《国家科学院院刊》(PNAS)上。
“这项研究将帮助我们确定手术时一位贫血患者在什么时候会有受损伤和死亡的最大危险。”黑尔说。“验证这一结论的人类研究正在进行中。”(生物谷 Bioon.com)
doi:10.1073/pnas.1114026108
PMC:
PMID:
Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia
Tsui, Albert K. Y.; Marsden, Philip A.; Mazer, C. David; Adamson, S. Lee; Henkelman, R. Mark; Ho, J. J. David; Wilson, David F.; Heximer, Scott P.; Connelly, Kim A.; Bolz, Steffen-Sebastian; Lidington, Darcy; El-Beheiry, Mostafa H.; Dattani, Neil D.; Chen, Kevin M.; Hare, Gregory M. T.
Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS)−/− mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS−/− mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS−/− mice, despite comparable reductions in tissue PO2. Paradoxically, nNOS−/− mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S-nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S-nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.