Nitric Oxide in Human Health and Disease

Abstract

Nitric oxide (NO) is a free radical, actively produced in human body. NO exerts crucial roles in vascular and neuronal signal transduction, smooth muscle contractility, bioenergetics, platelet adhesion and aggregation, immunity, and cell death regulation. The evidence accumulated over the last 25 years suggests that a defective control of the NO levels causes pathologies, such as hypertension, cardiovascular dysfunctions, neurodegeneration, arthritis, asthma and septic shock. Despite dealing with NO, the boundary between health and disease is still blurry, although the feeling is that pulses of NO in the low concentration range (piconanomolar) are by and large physiological, whereas cell persistence in the high concentration range (micromolar) may turn to pathological. Evidence is growing that the dark side of NO resides on its concentration levels and on the production of peroxynitrite and other reactive oxygen and nitrogen species; last but not least, the type of biomolecule reacting with NO and, when present, the cell bioenergetic changes induced strongly contribute to physiological or pathological outcomes.

Key Concepts:

  • Nitric oxide shares with O2 and towards biomolecules, high reactivity and duality of effects, both beneficial and detrimental.

  • In the human body, a variety of metabolic effects are induced by NO, owing to the widespread nitrergic signalling and bioenergetic chemistry.

  • It is time to verify whether the S‐nitrosation of proteins and enzymes is as important as their phosphorylation.

  • The NO chemistry in the human body appears tightly integrated with the chemistry of H2S and CO.

  • The intracellular NO and O2−• concentration, both absolute and relative, are vital to cell redox homoeostasis: it is their imbalance that triggers pathological responses.

  • Sometimes, the NO released by one isoform antagonises the effects of NO produced by another isoform. During cerebral ischaemia, for instance, the nNOS appears involved in tissue injury, whereas the eNOS preserves blood flow and tissue oxygenation.

  • The mechanism of macromolecular damage by peroxynirite is still poorly understood.

  • Feeling is growing that besides the oxidative stress, a reductive stress should be also considered.

  • For how long should a cell Ca++ transient lasts to stimulate cNOS? Moreover, is amplitude and duration of such a stimulus different in physiology and pathology?

Keywords: radical chemistry; nitrosative stress; bioenergetics; nitrergic transmission; neurodegeneration; mitochondria; haem proteins pathophysiology; warburg effect; melatonin; molecular mechanisms

Figure 1.

Cell targets of NO and reactive nitrogen–oxygen species. Top pathway: reactions leading, predominantly, to physiological outcomes, contrary to bottom pathway where pathological effects are induced particularly by an early formation of RONS and ONOO. The affinity of NO for the targets decreases from left to right. sGC, soluble guanylate cyclase; CcOX, cytochrome c oxidase; Nht, nonheme targets; RONS, reactive oxygen and nitrogen species; Prt, proteins; Lip, lipids; Nac, nucleic acids and FeS centres. Modified by permission of Hill et al. © The American Society for Biochemistry and Molecular Biology.

Figure 2.

Nitrergic signal transmission within the neuroeffector junction and at the endothelium smooth muscle cell interface. The NO released from a nerve terminal and an endothelial cell stimulates the production of cGMP, with activation of PKG. Simplified schematic representation of the smooth muscle cell relaxation sequence of reactions.

Figure 3.

Heart disease deaths by sex: age distribution and eNOS expression. (a) Ratios calculated according to the California Department of Public Health on the Heart Disease Mortality Data Trends (California 2000–2008), available online at: http://www.cdph.ca.gov/programs/ohir/Pages/Heart2008PrinterVersion.aspx (b) eNOS expression (western blot analysis) in the endothelial cells from the internal mammal artery of postmenopausal women versus aged man (*P<.001). Modified by permission of Mannacio et al. © Elsevier.

Figure 4.

Nitric oxide and the penile erection. Following sexual stimulus, NO is released in nonadrenergic noncholinergic (NANC) fibres as well as from endothelial eNOS at the level of pudendal arteries and cavernosal smooth muscle cells. Arteries relaxation and veins compression (against tunica albuginea) result in a greater inflow of blood relative to outflow. As a consequence, the intracavernosal blood pressure rises and erection occurs. Reproduced with permission from Jeremy et al. © Nature Publishing Group.

Figure 5.

Nitric oxide in the synaptic signal transmission. At synaptic level, the presynaptic stimulus induces depolarisation of postsynaptic terminal (ΔΨ), the process requiring the mobility of small cations (K +and Na+); concomitantly, glutamate is released, inducing the N‐methyl‐D‐aspartate receptors (NMDAr) to release Mg++ and allow [Ca2+]i to rise. This causes neuronal nitric oxide synthase (nNOS) to synthesise NO; the back diffusion of NO induces the sGC activation with further glutamate release and potentiation of the signal.

Figure 6.

Nitric oxide and mitochondrial oxygen reactive species. According to Moncada and Erusalimsky (), a temporary inhibition of cytochrome c oxidase by NO may lead to enhancement of superoxide anion (O2) and thereby of H2O2 acting as a signalling molecule (top panel). When inhibition by NO persists, the concentration of cell detrimental ONOO rises (bottom). Modified by permission of Brunori et al. © Elsevier.

Figure 7.

Expression of iNOS in chronic active human multiple sclerosis (MS) plaques. (a) Active periventricular lesion showing iNOS expression (green) along the ventricle (lower border) and around a blood vessel (V). The arrow indicates a region of normal white matter close to lesion. Single * indicates the area magnified in (b) and (**) the border of the plaque, with some green fluorescence, and including inflammatory cells (red) are also seen nearby the lesion. (V) indicates the vessel (4x). (b) Cellular inflammatory infiltration of the MS plaque, A * area. iNOS (green) cell surface macrophage/microglia marker CD64 (red) (magnification 60x). (c) Perivascular iNOS expression near a plaque (40x). (d) Periventricular section of a chronic active lesion showing ependymal cells, marked in red (perinuclear glial fibrillar acid protein, GFAP), with diffuse intracellular iNOS expression (100x). (Cell nucleus=blue); (Lipofuscin=white). Modified by permission of Hill et al. © Elsevier.

Figure 8.

NO oxidation products in synovial fluids of humans and experimental animals. (Top) Nitrite and nitrate levels in synovial exudates of zymosan‐induced arthritis of the rat temporomadibular joint. Modified with permission from Chaves et al. © Helliada Vasconcelos Chaves. (Bottom) Nitrite concentration in synovial fluid (SF) and serum (SR) samples of patients with rheumatoid arthritis (RA) and osteo arthritis (OA). Modified by permission of Farrell et al. © BMJ publishing group.

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References

Almeida A, Almeida J, Bolanos JP and Moncada S (2001) Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proceedings of the National Academy of Sciences of the USA 98(26): 15294–15299.

Araujo JA, Zhang M and Yin F (2012) Heme oxygenase‐1, oxidation, inflammation, and atherosclerosis. Frontiers in Pharmacology 3: 119.

Arese M, Magnifico MC, Mastronicola D et al. (2012) Nanomolar melatonin enhances nNOS expression and controls HaCaT‐cells bioenergetics. IUBMB Life 64: 251–258.

Arnold WP, Mittal CK, Katsuki S and Murad F (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3′5′‐cyclic monophosphate levels in various tissue preparations. Proceedings of the National Academy of Sciences of the USA 74(8): 3203–3207.

Bates TE, Loesch A, Burnstock G and Clark JB (1996) Mitochondrial nitric oxide synthase: a ubiquitous regulator of oxidative phosphorylation? Biochemical and Biophysical Research Communications 218(1): 40–44.

Bellamy TC, Wood J and Garthwaite J (2002) On the activation of soluble guanylyl cyclase by nitric oxide. Proceedings of the National Academy of Sciences of the USA 99(1): 507–510.

Bonacci G, Schopfer FJ, Batthyany CI et al. (2011) Electrophilic fatty acids regulate matrix metalloproteinase activity and expression. Journal of Biological Chemistry 286(18): 16074–16081.

Brown GC and Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Letters 356(2–3): 295–298.

Brunori M, Forte E, Arese M et al. (2006) Nitric oxide and the respiratory enzyme. Biochimica et Biophysica Acta 1757(9‐10): 1144–1154.

Chaves HV, Ribeiro Rde A, de Souza AM et al. (2011) Experimental model of zymosan‐induced arthritis in the rat temporomandibular joint: role of nitric oxide and neutrophils. Journal of Biomedicine and Biotechnology 2011: 707985.

Cho S, Park EM, Zhou P et al. (2005) Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. Journal of Cerebral Blood Flow & Metabolism 25(4): 493–501.

Clementi E, Brown GC, Feelisch M and Moncada S (1998) Persistent inhibition of cell respiration by nitric oxide: crucial role of S‐nitrosylation of mitochondrial complex I and protective action of glutathione. Proceedings of the National Academy of Sciences of the USA 95(13): 7631–7636.

Domek‐Lopacinska KU and Strosznajder JB (2010) Cyclic GMP and nitric oxide synthase in aging and Alzheimer's disease. Molecular Neurobiology 41(2‐3): 129–137.

Farrell AJ, Blake DR, Palmer RM and Moncada S (1992) Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Annals of the Rheumatic Diseases 51(11): 1219–1222.

Fernandez‐Vizarra P, Fernandez AP and Castro‐Blanco S (2004) Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Neurobiology of Disease 15(2): 287–305.

Fleming I (2010) Molecular mechanisms underlying the activation of eNOS. Pflügers Archiv 459(6): 793–806.

Forstermann U and Sessa WC (2011) Nitric oxide synthases: regulation and function. European Heart Journal 33(7): 829–837.

Forte E, Urbani A, Saraste M et al. (2001) The cytochrome cbb3 from Pseudomonas stutzeri displays nitric oxide reductase activity. European Journal of Biochemistry 268(24): 6486–6491.

Gorodeski GI (1994) Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women. Experimental Gerontology 29(3–4): 357–375.

Hall CN and Garthwaite J (2009) What is the real physiological NO concentration in vivo? Nitric Oxide 21(2): 92–103.

Herman AG and Moncada S (2005) Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis. European Heart Journal 26(19): 1945–1955.

Hill BG, Dranka BP, Bailey SM, Lancaster JR Jr. and Darley‐Usmar VM (2010) What part of NO don't you understand? Some answers to the cardinal questions in nitric oxide biology. Journal of Biological Chemistry 285(26): 19699–19704.

Hill KE, Zollinger LV, Watt HE, Carlson NG and Rose JW (2004) Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. Journal of Neuroimmunology 151(1–2): 171–179.

Huang PL (2000) Mouse models of nitric oxide synthase deficiency. Journal of the American Society of Nephrology 11(suppl. 16): S120–S123.

Iadecola C, Zhang F, Casey R, Clark HB and Ross ME (1996) Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27(8): 1373–1380.

Ignarro LJ, Buga GM, Wood KS, Byrns RE and Chaudhuri G (1987) Endothelium‐derived relaxing factor produced and released from artery and vein is nitric oxide. Proceedings of the National Academy of Sciences of the USA 84(24): 9265–9269.

Jeremy JY, Jones RA and Koupparis AJ (2007) Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase. International Journal of Impotence Research 19(3): 265–280.

Kleinbongard P, Schulz R and Rassaf T (2006) Red blood cells express a functional endothelial nitric oxide synthase. Blood 107(7): 2943–2951.

Kostikas K, Minas M, Papaioannou AI, Papiris S and Dweik RA (2011) Exhaled nitric oxide in asthma in adults: the end is the beginning? Current Medicinal Chemistry 18(10): 1423–1431.

Kummer MP, Hermes M, Delekarte A et al. (2011) Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron 71(5): 833–844.

Li CG and Rand MJ (1991) Evidence that part of the NANC relaxant response of guinea‐pig trachea to electrical field stimulation is mediated by nitric oxide. British Journal of Pharmacology 102(1): 91–94.

Li H and Forstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. Journal of Pathology 190(3): 244–254.

Lonn ME, Dennis JM and Stocker R (2012) Actions of ‘antioxidants’ in the protection against atherosclerosis. Free Radical Biology and Medicine 53(4): 863–884.

Lundberg JO, Weitzberg E and Gladwin MT (2008) The nitrate‐nitrite‐nitric oxide pathway in physiology and therapeutics. Nature Reviews Drug Discovery 7(2): 156–167.

Mannacio V, Di Tommaso L, Antignano A et al. (2012) Endothelial nitric oxide synthase expression in postmenopausal women: a sex‐specific risk factor in coronary surgery. The Annals of Thoracic Surgery 94: 1934–1939.

Mason MG, Nicholls P, Wilson MT and Cooper CE (2006) Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase. Proceedings of the National Academy of Sciences of the USA 103(3): 708–713.

Mellion BT, Ignarro LJ, Ohlstein EH et al. (1981) Evidence for the inhibitory role of guanosine 3′, 5′‐monophosphate in ADP‐induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 57(5): 946–955.

Moncada S and Erusalimsky JD (2002) Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nature Reviews Molecular Cell Biology 3(3): 214–220.

Nossaman B, Pankey E and Kadowitz P (2012) Stimulators and activators of soluble guanylate cyclase: review and potential therapeutic indications. Critical Care Research and Practice 2012: 290805.

Oddi S, Latini L, Viscomi MT et al. (2012) Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration. Journal of Molecular Medicine 90(4): 371–387.

Palmer RM, Ferrige AG and Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium‐derived relaxing factor. Nature 327(6122): 524–526.

Qu J, Nakamura T, Holland EA, McKercher SR and Lipton SA (2012) S‐nitrosylation of Cdk5: potential implications in amyloid‐beta‐related neurotoxicity in Alzheimer disease. Prion 6(4): 364–370.

Samdani AF, Dawson TM and Dawson VL (1997) Nitric oxide synthase in models of focal ischemia. Stroke 28(6): 1283–1288.

Santos RM, Lourenco CF, Ledo A, Barbosa RM and Laranjinha J (2012) Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. International Journal of Cell Biology 2012: 391914.

Sarti P, Forte E, Mastronicola D, Giuffre A and Arese M (2012a) Cytochrome c oxidase and nitric oxide in action: molecular mechanisms and pathophysiological implications. Biochimica et Biophysica Acta 1817: 610–619.

Sarti P, Forte E, Giuffre A et al. (2012b) The chemical interplay between nitric oxide and mitochondrial cytochrome c oxidase: reactions, effectors and pathophysiology. International Journal of Cell Biology 2012: 571067.

Sarti P, Giuffrè A, Forte E et al. (2000) Nitric oxide and cytochrome c oxidase: mechanisms of inhibition and NO degradation. Biochemical and Biophysical Research Communications 274(1): 183–187.

Stuehr D J (1997) Structure–function aspects in the nitric oxide synthases. Annual Review of Pharmacology and Toxicology 37: 339–359.

Vasquez‐Vivar J (2009) Tetrahydrobiopterin, superoxide, and vascular dysfunction. Free Radical Biology and Medicine 47(8): 1108–1119.

Wang R (2002) Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB Journal 16(13): 1792–1798.

Wang X, Cao J, Wang X et al. (2012) Exogenous carbon monoxide attenuates inflammatory responses in the small intestine of septic mice. World Journal of Gastroenterology 18(40): 5719–5728.

Wiskur B and Greenwood‐Van Meerveld B (2010) The aging colon: the role of enteric neurodegeneration in constipation. Current Gastroenterology Reports 12(6): 507–512.

Further Reading

Antonopoulos AS, Margaritis M, Lee R, Channon K and Antoniades C (2012) Statins as anti‐inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Current Pharmaceutical Design 18(11): 1519–1530.

Chan KY, Vermeersch S, de Hoon J, Villalon CM and Maassenvandenbrink A (2011) Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects. Pharmacology & Therapeutics 129(3): 332–351.

Feletou M, Kohler R and Vanhoutte PM (2012) Nitric oxide: Orchestrator of endothelium‐dependent responses. Annals of Medicine 44(7): 694–716.

Frohman EM, Racke MK and Raine CS (2006) Multiple sclerosis‐the plaque and its pathogenesis. The New England Journal of Medicine 354(9): 942–955.

Hurt KJ, Sezen SF, Lagoda GF et al. (2012) Cyclic AMP‐dependent phosphorylation of neuronal nitric oxide synthase mediates penile erection. Proceedings of the National Academy of Sciences of the United States of America 109(41): 16624–16629.

Lau A and Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv: European Journal of Physiology 460(2): 525–542.

Novella S, Dantas AP, Segarra G, Medina P and Hermenegildo C (2012) Vascular aging in women: is estrogen the fountain of youth? Front Physiology 3: 165.

Petersson J, Phillipson M, Jansson EA et al. (2007) Dietary nitrate increases gastric mucosal blood flow and mucosal defense. American Journal of Physiology. Gastrointestinal and Liver Physiology 292(3): G718–G724.

Poyton RO, Castello PR, Ball KA, Woo DK and Pan N (2009) Mitochondria and hypoxic signaling: a new view. Annals of the New York Academy of Sciences 1177: 48–56.

Rudolph V and Freeman BA (2009) Cardiovascular consequences when nitric oxide and lipid signaling converge. Circulation Research 105(6): 511–522.

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Paolo, Sarti(Apr 2013) Nitric Oxide in Human Health and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003390.pub2]