| |
[摘要]：The identification of nitric oxide ((NO)-N-center dot) 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)-N-center dot ligation of the heme iron of soluble guanylate cyclase is consistent with this perspective, the readily diffusible and broadly reactive (NO)-N-center dot 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 antiinflammatory 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)-N-center dot that are guanylate cyclase-independent and rather are dictated by anatomic distribution and the formation of secondary (NO)-N-center dot-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)-N-center dot and other oxides of nitrogen, lipid signaling mechanisms are a significant target for regulation by (NO)-N-center dot in the vascular compartment. This convergence of (NO)-N-center dot and lipid signaling pathways thus adds another level of regulation to physiological responses such as vasodilation, thrombosis, and inflammation. Herein, interactions between (NO)-N-center dot and lipid signaling events are placed in the context of cardiovascular regulation. (Circ Res. 2009; 105: 511-522.) |
|
