Two Faces of Nitric Oxide

Nitric oxide synthases (NOSs) comprise a family of enzymes that generate the freely diffusible, free radical gas NO, by the conversion of l-arginine to l-citrulline in the presence of O2 and NADPH. Bioactive derivatives of NO (NOx) are produced depending on the redox state of the cell and the availability of substrates and cofactors.1 The three NOSs arise from separate genes, but each NOS molecule is composed of a calmodulin binding domain that links a carboxyl terminal flavin-containing reductase domain with an amino terminal heme-containing oxygenase domain.1 Neuronal NOS (or NOS1) and endothelial NOS (or NOS3) are constitutively active isoforms with calmodulin binding (and, consequently, enzyme activity) regulated by physiological [Ca2+], whereas inducible NOS (iNOS or NOS2) binds calmodulin tightly, even at physiological [Ca2+].1Each of the three NOS isoforms is present in the heart, undergoes posttranslational modification, and is spatially constrained within the cell. NOS1 expression is limited and its physiological role is unclear. The largest sources in the heart of the cytokine (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and lipopolysaccharide-inducible NOS2 are from cardiac myocytes, endothelial cells, and infiltrating macrophages. NOS3 is found in the endocardial and coronary arterial endothelium, myocytes, and specialized cardiac conduction tissue.1Constitutive expression of NO is protective. Vascular effects include vasodilatation, inhibition of platelet adhesion and neutrophil infiltration, prevention of neointimal proliferation, and inhibition of vascular remodeling in heart. Cardiac effects of constitutive NO include regulation of the coronary circulation, heart rate, and contractility. In …