加拿大多倫多圣米高醫(yī)院的研究人員發(fā)現(xiàn)一種酶有新的作用,，它有可能會保護(hù)因為貧血引起的損傷和死亡。
該醫(yī)院李嘉誠知識研究所研究員格雷戈黑爾說,，“發(fā)現(xiàn)這一機(jī)制有可能為貧血病人帶來新的治療并改善治療的效果,。”
世界四分之一的人以及50%手術(shù)病人會有貧血。造成貧血的原因不同,，包括感染（瘧疾,、HIV和寄生蟲）、營養(yǎng)不良（鐵,、葉酸和B12）,、遺傳變異、懷孕,、創(chuàng)傷和手術(shù)失血,。當(dāng)血液中紅細(xì)胞或血紅蛋白（從肺和心臟攜帶氧到身體其它部位的一種富含鐵蛋白）數(shù)量低于正常就會發(fā)生貧血。細(xì)胞需要氧來生存和產(chǎn)生所有人體功能所需的能量,。
黑爾博士和他的同事們發(fā)現(xiàn),，當(dāng)人體出現(xiàn)貧血時，神經(jīng)元的一氧化氮合成酶（神經(jīng)細(xì)胞中能產(chǎn)生重要信號分子一氧化氮的酶）會增加人體的反應(yīng)能力,，使人體適應(yīng)低氧狀態(tài)并更有效地釋放氧到組織,。研究人員發(fā)現(xiàn)，在貧血的小鼠大腦中一氧化氮合成酶水平會增加,，而那些沒有這種酶的小鼠會過早死亡,。
這項研究發(fā)表在美國《國家科學(xué)院院刊》（PNAS）上,。
“這項研究將幫助我們確定手術(shù)時一位貧血患者在什么時候會有受損傷和死亡的最大危險。”黑爾說,。“驗證這一結(jié)論的人類研究正在進(jìn)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.
