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Andrew Johan*

SUMMARY

Nitric Oxide (NO) is produced in higher organisms by the oxidation of one of the terminal guanido-nitrogen atoms of L-arginine. Nitric Oxide Synthase (NOS) catalyzes the oxidation of arginine to NO and citrulline. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen (O2) are required as co-substrates.

NOS exists in three distinct isoforms: 1. constitutive neuronal NOS (NOS I or nNOS), 2. inducible NOS (NOS II or

iNOS), and 3. constitutive endothelial NOS (NOS III or eNOS).   The three NOS isoforms can be regulated by various stimuli. iNOS isoform is regulated at a pretranslational level and can be induced by proinflammatory cytokines, such as tumor necrosis factor a (TNFa), gamma interferon (IFNg), and interleukin (IL)1b. nNOS regulation are correlated with the response of neuronal cells to stress induced by physical, chemical, and biological agents such as heat, electrical stimulation, light exposure, and allergic substances. eNOS activity are correlated with the increase in intracellular Ca2+ concentration.

Nitric oxide is an important mediator of homeostatic processes and host defense mechanisms. Changes in its

generation or actions contribute to pathologic states. How changes in the concentration of L-arginine influence the initiation, development, and resolution of some of these pathologic conditions remains to be elucidated. It seems that increased ingestion of L-arginine reverses the changes in host defense mechanisms, vascular reactivity and may also reduce blood pressure .

SYNTHESIS OF NO

Nitric Oxide (NO) is produced in higher organisms by the oxidation of one of the terminal guanido-nitrogenatoms

of L-arginine.1 NOS exists in three distinct isoforms:

  1. constitutive neuronal NOS (NOS I or nNOS),
  2. inducible NOS (NOS II or iNOS),
  3. constitutive endothelial NOS (NOS III or eNOS).

Protein purification and molecular cloning approaches have identified the three distinct isoforms of NOS. nNOS, iNOS, and eNOS are products of distigenes located on different human chromosomes (12, 17, and 7 chromosomes, respectively), each with a characteristic pattern of tissue-specific expression.2

Fig. 1. The Oxidation of Arginine to No and Citrulline.

Nitric oxide synthase (NOS) catalyzes the oxidation of arginine to no and citrulline. NADPH and O2 are required as co-substrates.

 

 

iNOS isoform is regulated at a pretranslational level and can be induced by proinflammatory cytokines, such as tumor necrosis factor a (TNFa), gamma interferon (IFNg), and interleukin (IL)1b (Fig. 2). 3,4

I n d u c t i o n o f m a c r o p h a g e i N O S m R N A b y

lipopolysacharide (LPS) plus IFNg reflects increased iNOS gene transcription.3 LPS activates the mitogen-activated protein (MAP) kinase pathway with subsequent activation of NFB through phosphorylation and degradation of IB.5

IFNg signaling to gene expression begins with a specific receptor interaction followed by the Janus kinase (JAK)- STAT1 pathway that involves a tyrosine phosphorylation cascade.6   Pretreatment with genistein, a tyrosine kinase inhibitor, prevents IFNg induction of iNOS expression in airway epithelial cells. Transforming growth factor (TGFa) suppresses macrophage iNOS expression via decreased iNOS mRNA stability and translational efficiency and by decreased stability of iNOS protein. Changes in NO production are correlated with similar changes in iNOS mRNA, indicating that a major part of iNOS regulation occurs at transcription step. 3

 

nNOS and eNOS isoforms

nNOS regulation are correlated with the response of neuronal cells to stress induced by physical, chemical, and biological agents such as heat, electrical stimulation, light exposure, and allergic substances. Enhanced nNOS expression is often associated with coinduction

 






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