Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice

Abstract

Nitric oxide (NO) is a gaseous molecule that plays many key roles in the cardiovascular system. Each of the enzymes that generate NO--neuronal, inducible and endothelial NO synthase-has been genetically disrupted in mice. This review discusses the cardiovascular phenotypes of each of the NO synthase (NOS) gene knockout mice, and the insights gained into the roles of NO in the cardiovascular system. Mice lacking the endothelial isoform are hypertensive, have endothelial dysfunction and show a more severe outcome in response to vascular injury, to stroke and cerebral ischaemia, and to diet-induced atherosclerosis. Mice lacking the neuronal isoform show a less severe outcome in response to stroke and cerebral ischaemia but have increased diet-induced atherosclerosis. Mice lacking the inducible isoform show reduced hypotension to septic shock. Together, NOS gene knockout mice have been useful tools that complement our other approaches to studying the multiple roles of NO in the cardiovascular system.

Figure 1

Regulation of eNOS activity and mechanisms for endothelial dysfunction. Several mechanisms can account for endothelial dysfunction, including: (1) changes in eNOS mRNA or protein levels; (2) decreased substrate availability; (3) decreased cofactor availability; (4) improper subcellular localization; (5) abnormal phosphorylation; and (6) scavenging of NO by superoxide $({\text{O}}_2^{-})$ to form peroxynitrite anion (ONOO⁻). ADMA, asymmetric dimethylarginine; SOD, superoxide dismutase; PKG, protein kinase G.

Figure 2

eNOS and nNOS in cardiac excitation–contraction coupling. In cardiac myocytes, eNOS associates with caveolin-3 at the sarcolemma, where it blunts inotropic response to isoproterenol stimulation. nNOS associates with the ryanodine receptor at the sarcoplasmic reticulum and is required for proper Ca²⁺-mediated Ca²⁺ release. Arrow thickness reflects magnitude of Ca²⁺ flux. Cav3, caveolin-3; β-AR, β-adrenergic receptor; RyR, ryanodine receptor; FKBP, FK506-binding protein; PLB, phospholamban; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase.