Nitric Oxide in Health & Diseases (Commentary) (Nitric Oxide Synthase)

Nitric Oxide in Health & Diseases (Commentary) (Nitric Oxide Synthase)

Nitric oxide (NO) a byproduct of the oxidative reaction catalysed by nitric oxide synthase (NOS) that converts L-arginine to citrulline, act as a pleiotropic mediator in various physiological and pathophysiological conditions. The gaseous free radical, nitric oxide (half life 15 sec) is readily oxidised to N[O.sub.2] and N[O.sub.3.sup.-], and is highly reactive to free thiols and transition metal ions. Nitric oxide synthase has three major isoforms, neuronal (nNOS) and endothelial (eNOS) being constitutive, inducible (iNOS) is expressed only following the induction by the inflammatory mediators such as lipopolysaccharidc (LPS), interleukins (IL-1, IL-11) and tumour necrosis factor (TNF-[alpha]). Cells that contain isoforms of NOS, the agents that activate and inhibit them, and the molecules with which their products interact, trigger a diverse of physiological effects in mammals (1). In addition to its role in regulating vessel tone, blood vessel dilatation, neurotransmission, modulation of the hair cycle, and penile erections, NO plays a vital role in host defence and immunity, including the modulation of inflammatory responses. The expression of iNOS is regulated by the balance of cytokines in the microenvironment; for example, transforming growth factor p (TGFP), IL-4, and IL-10 inhibit iNOS expressions in macrophages. Interestingly, iNOS can be expressed in many cells when they are exposed to stimulatory cytokines, including cells that constitutively express eNOS. A key concept is that there are species and cell variability with regard to the regulation of iNOS expression (2). For example, in vitro, while iNOS is readily induced by IL-1[beta] and TNF-[alpha] in murine macrophages, human monocytes and macrophages have been demonstrated to express iNOS in a variety of disease states, including rheumatoid arthritis (RA), malaria, and vasculitis, suggesting that in vivo when exposed to the requisite stimuli, these cells are capable of iNOS upregulation (3-5), where many pathological conditions are the manifestations of elevated NO. In such conditions suppression of iNOS is found to be effective, although many chemical inhibitors of iNOS are available but recently more efficient suppression of iNOS at post-transcriptional level by using DNAzymes specific to iNOS mRNA has been shown to be successful both in vitro and in vivo (6). Recent insight has been provided by reports that interferon-[gamma] (IFN [gamma]) can induce iNOS messenger RNA (mRNA) and protein in human monocytes both in vivo (patients undergoing treatment for chronic hepatitis C) and in vitro.

Nitric Oxide in Health & Diseases (Commentary) (Nitric Oxide Synthase)



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