Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences

Abstract

The different cell types comprising cardiac muscle express one or more of the three isoforms (neuronal NOS, or nNOS; inducible NOS, or iNOS; and endothelial NOS, or eNOS) of nitric oxide synthase (NOS). nNOS is expressed in orthosympathetic nerve terminals and regulates the release of catecholamines in the heart. eNOS constitutively expressed in endothelial cells inhibits contractile tone and the proliferation of underlying vascular smooth muscle cells, inhibits platelet aggregation and monocyte adhesion, promotes diastolic relaxation, and decreases O2 consumption in cardiac muscle through paracrinally produced NO. eNOS is also constitutively expressed in cardiac myocytes from rodent and human species, where it autocrinally opposes the inotropic action of catecholamines after muscarinic cholinergic and beta-adrenergic receptor stimulation. iNOS gene transcription and protein expression are induced in all cell types after exposure to a variety of inflammatory cytokines. Aside from participating in the immune defense against intracellular microorganisms and viruses, the large amounts of NO produced autocrinally or paracrinally mediate the vasoplegia and myocardial depression characteristic of systemic immune stimulation and promote cell death through apoptosis. In cardiac myocytes, NO may regulate L-type calcium current and contraction through activation of cGMP-dependent protein kinase and cGMP-modulated phosphodiesterases. Other mechanisms independent of cGMP elevations may operate through interaction of NO with heme proteins, non-heme iron, or free thiol residues on target signaling proteins, enzymes, or ion channels. Given the multiplicity of NOS isoforms expressed in cardiac muscle and of the potential molecular targets for the NO produced, tight molecular regulation of NOS expression and activity at the transcriptional and posttranscriptional level appear to be needed to coordinate the many roles of NO in heart function in health and disease.