Cardiovascular consequences when nitric oxide and lipid signaling converge

Abstract

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 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 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.

Figure 1. Reaction rate constants for critical reactions of •NO and •NO-derived species with key molecular targets that transduce cell signaling events

Figure 2. Formation of lipid signaling mediators from redox reactions within the lipid core of lipoproteins or cell membranes

(1) Oxidation of membrane lipids by free radicals and oxidants initiate lipid peroxidation, by formation of lipid radical species that then react with molecular oxygen or other radicals to form lipid peroxyl radicals. Peroxyl radical species can then either further propagate lipid peroxidation events or they can (2) serve as precursors for the generation of isoprostanes and reactive aldehyde derivatives. Finally, both native fatty acids or oxidized fatty acids can react with nitrogen dioxide (•NO₂) arising from secondary reactions of •NO and nitrite (NO₂⁻) leading to the formation of nitro-fatty acid derivatives (3)