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(Circulation Research. 2009;105:511.)
© 2009 American Heart Association, Inc.

Review

Cardiovascular Consequences When Nitric Oxide and Lipid Signaling Converge

Volker Rudolph, Bruce A. Freeman

From the Department of Pharmacology and Chemical Biology (V.R., B.A.F.), University of Pittsburgh, Pa; and the Department of Cardiology (V.R.), University Heart Center Hamburg, Germany.

Correspondence to Bruce A. Freeman, PhD, Department of Pharmacology & Chemical Biology, E1340 Thomas E. Starzl Biomedical Science Tower, 200 Lothrop St, University of Pittsburgh, Pittsburgh, PA 15213. E-mail freerad{at}pitt.edu

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.

Key Words: nitric oxide • lipids • redox reaction • fatty acids • cardiovascular