来自美国弗吉尼亚大学的科研人员日前的研究为上皮细胞中NO信号的调控提供了新的模型,上皮血红蛋白α的氧化状态调控NO的生物活性和向血管平滑肌靶点的弥散。

-2012年11月15日《自然》

中文翻译


【题目】上皮细胞表达血红蛋白α来调控一氧化氮信号

【译文】非调控一氧化氮(NO)扩散的模型并非始终承担许多细胞体系中NO合酶(NOS)依赖的信号的生化特性。例如,上皮NOS通过其对血管平滑肌紧张度控制血压、血流量和氧输送,但这些过程的调控不能被单一NO从内皮到平滑肌的扩散所充分阐释。本研究通过证实血红蛋白(Hb) α(由人HBA1和HBA2基因编码)在人和鼠动脉上皮细胞中表达并在肌内皮连接处含量丰富,发现了NO信号调控的新模型,在肌内皮连接处,血红蛋白α可以调控NO对血管反应性的影响。值得注意的是,这种功能是Hb α所特有的,并通过基因敲除而被消除。机制上说,Fe3+状态的上皮Hb α血红素铁形成NO信号,当Hb α通过内皮细胞色素b5还原酶3(CYB5R3,又称为硫辛酸脱氢酶1)被还原为Fe2+状态时该信号被关闭。CYB5R3的遗传和药理学抑制增加了小动脉中NO生物活性。这些数据揭示了一种新的机制,据此,胞内Hb α氧化状态的调控控制着非红系细胞中NOS信号。该模型可能与大量的含NOS体细胞中含血红素的球蛋白相关。

英文原稿


[Title]: Endothelial cell expression of haemoglobin α regulates nitric oxide signaling

[Authors]:Adam C. Straub,1 Alexander W. Lohman,1, 2 Marie Billaud,1, 2 Scott R. Johnstone,1 Scott T. Dwyer,3 Monica Y. Lee,1 Pamela Schoppee Bortz,1 Angela K. Best,1 Linda Columbus,4 Benjamin Gaston3 & Brant E. Isakson1, 2

[Abstract]Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) α (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to Hb α and is abrogated by its genetic depletion. Mechanistically, endothelial Hb α haem iron in the Fe3+ state permits NO signalling, and this signalling is shut off when Hb α is reduced to the Fe2+ state by endothelial cytochrome b5 reductase 3 (CYB5R3, also known as diaphorase 1). Genetic and pharmacological inhibition of CYB5R3 increases NO bioactivity in small arteries. These data reveal a new mechanism by which the regulation of the intracellular Hb α oxidation state controls NOS signalling in non-erythroid cells. This model may be relevant to haem-containing globins in a broad range of NOS-containing somatic cells.

原文地址

http://www.nature.com/nature/journal/v491/n7424/full/nature11626.html

 

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