Cardiovascular consequences when nitric oxide and lipid signaling converge.
Cardiovascular consequences when nitric oxide and lipid signaling converge.
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DOI：
10.1161/circresaha.109.202077
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发表时间：
2009-09-11
影响因子：
20.1
通讯作者：
Freeman BA
中科院分区：
文献类型：
--
作者：
Rudolph V;Freeman BA
一氧化氮（•NO）作为内皮依赖性松弛和宿主防御的内源性自由基介体的鉴定从根本上改变了细胞信号转导的概念。面向配体受体的细胞信号传导范式最初以配体与其受体之间的高亲和力和特异性相互作用的概念为中心，导致次级信号传导事件的激活，例如基因表达或催化蛋白功能的调节。虽然可溶性鸟苷酸环化酶的血红素铁的NO连接与这一观点一致，但易于扩散和广泛反应的NO越来越被认为与大量靶分子反应，这些靶分子介导旁分泌血管舒张作用、抑制血栓形成和新内膜增殖以及不受可溶性鸟苷酸环化酶抑制剂影响的促炎和抗炎信号反应。由•NO 介导的功能显着的“脱靶”附带反应不断扩大，这些反应与鸟苷酸环化酶无关，而是由解剖分布和次级•NO 衍生物质的形成决定。这些反应是氧化还原调节信号传导的关键要素，并且在本文中在不饱和脂肪酸氧化为血管和炎症信号传导介质的背景下进行讨论。由于不饱和脂质中间体和类二十烷酸代谢酶的丰富性以及与NO 和其他氮氧化物的内在反应性，脂质信号传导机制是血管室中NO 调节的重要目标。 •NO 和脂质信号传导途径的这种融合，为血管舒张、血栓形成和炎症等生理反应增加了另一个层面的调节。在此，NO 和脂质信号传导事件之间的相互作用被置于心血管调节的背景下。
The identification of nitric oxide (•NO) as an endogenously produced free radical mediator of endothelial-dependent relaxation and host defense has fundamentally changed concepts of cell signal transduction. Ligand-receptor oriented paradigms of cell signaling were originally centered on the concept of a high affinity and specific interaction between a ligand and its receptor, resulting in the activation of secondary signaling events such as gene expression or modulation of catalytic protein function. While •NO ligation of the heme iron of soluble guanylate cyclase is consistent with this perspective, the readily diffusible and broadly reactive •NO is increasingly appreciated to react with a vast array of target molecules that mediate paracrine vasodilator actions, inhibition of thrombosis and neointimal proliferation and both pro- and anti-inflammatory signaling reactions that are not affected by inhibitors of soluble guanylate cyclase. There is an expanding array of functionally significant “off target” collateral reactions mediated by •NO that are guanylate cyclase-independent and rather are dictated by anatomic distribution and the formation of secondary •NO-derived species. These reactions are a critical element of redox-regulated signaling and are addressed herein in the context of the oxidation of unsaturated fatty acids to vascular and inflammatory signaling mediators. Because of their abundance and the intrinsic reactivity of unsaturated lipid intermediates and eicosanoid metabolism enzymes with •NO and other oxides of nitrogen, lipid signaling mechanisms are a significant target for regulation by •NO in the vascular compartment. This convergence of •NO and lipid signaling pathways thus adds another level of regulation to physiological responses such as vasodilation, thrombosis and inflammation. Herein, interactions between •NO and lipid signaling events are placed in the context of cardiovascular regulation.