Nitric oxide synthase (NOS) exists in three established isoforms. NOS I (NOS1, ncNOS) was originally discovered in neurons. This enzyme and splice variants thereof have since been found in many other cells and tissues. NOS II (NOS2, iNOS) was first identified in murine macrophages, but can also be induced in many other cell types. NOS III (NOS3, ecNOS) is expressed mainly in endothelial cells. Whereas NOS II is a transcriptionally regulated enzyme, NOS I and NOS III are considered constitutively expressed proteins. However, evidence generated in recent years indicates that these two isoforms are also subject to expressional regulation. In view of the important biological functions of these isoforms, changes in their expression may have physiological and pathophysiological consequences. This review recapitulates compounds and conditions that modulate the expression of NOS I and NOS III, summarizes transcriptional and posttranscriptional effects that underlie these changes, and-where known-describes the molecular mechanisms leading to changes in transcription, RNA stability, or translation of these enzymes.

Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III).

Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)-NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.

Nitric oxide signalling in cardiovascular health and disease

Red blood cells express a functional endothelial nitric oxide synthase.

The vascular endothelium synthesises the vasodilator and anti-aggregatory mediator nitric oxide (NO) from L-arginine. This action is catalysed by the action of NO synthases, of which two forms are present in the endothelium. Endothelial (e)NOS is highly regulated, constitutively active and generates NO in response to shear stress and other physiological stimuli. Inducible (i)NOS is expressed in response to immunological stimuli, is transcriptionally regulated and, once activated, generates large amounts of NO that contribute to pathological conditions. The physiological actions of NO include the regulation of vascular tone and blood pressure, prevention of platelet aggregation and inhibition of vascular smooth muscle proliferation. Many of these actions are a result of the activation by NO of the soluble guanylate cyclase and consequent generation of cyclic guanosine monophosphate (cGMP). An additional target of NO is the cytochrome c oxidase, the terminal enzyme in the electron transport chain, which is inhibited by NO in a manner that is reversible and competitive with oxygen. The consequent reduction of cytochrome c oxidase leads to the release of superoxide anion. This may be an NO-regulated cell signalling system which, under certain circumstances, may lead to the formation of the powerful oxidant species, peroxynitrite, that is associated with a variety of vascular diseases.

Nitric oxide and the vascular endothelium.

Evaluation of some biochemical changes in diabetic patients.

Using Western blot and fluorescent immunocytochemistry, NOS III (or ecNOS) and NOS II (or iNOS), but no NOS I (or ncNOS), were identified in preparations of human platelets. Reverse-transcription polymerase chain reactions (RT-PCR) demonstrated NOS III mRNA, but no NOS II mRNA (which is short-lived) and no NOS I mRNA in platelets. Immunofluorescent staining of human bone marrow smears showed the presence of NOS III, but not NOS I in megakaryocytes. A subpopulation of megakaryocytes also expressed NOS II. In preparations of human neutrophils, immunocytochemistry demonstrated NOS I in all cells, whereas no NOS III was detected. The few NOS II positive cells were characterized as contaminating eosinophils. Similarly, in RT-PCR, transcripts for NOS I and NOS II, but not for NOS III, were identified. Thus, the constitutive NOS isoform in megakaryocytes and platelets is NOS III, whereas neutrophils express NOS I. Some megakaryocytes and eosinophils also express NOS II.

Identification of the NO Synthase isoforms Expressed in Human Neutrophil Granulocytes, Megakaryocytes and Platelets

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Identification of the NO Synthase isoforms Expressed in Human Neutrophil Granulocytes, Megakaryocytes and Platelets