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Gene Review

Nos2  -  nitric oxide synthase 2, inducible

Rattus norvegicus

Synonyms: Inducible NO synthase, Inducible NOS, NOS type II, Nitric oxide synthase, inducible, Nos2a, ...
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Disease relevance of Nos2

  • Upregulation of Nos2 may contribute to the inflammatory response that characterizes early atherogenesis and may, in part, account for the adverse vascular effects of hyperhomocysteinemia [1].
  • These data suggest that PARS activation due to iNOS induction (1) is involved in the energetic depletion of vascular smooth muscle cells that express iNOS and (2) contributes to the pathogenesis of vascular energetic and contractile failure in endotoxic shock [2].
  • Serum levels of NO and tumor necrosis factor alpha, key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals [3].
  • These results show that iNOS is predominantly expressed in polymorphonuclear leukocytes accumulating at 1 hour in the glomeruli of anti-Thy-1 glomerulonephritis and suggest an involvement of NO in the initiation of the disease [4].
  • However, the augmented expression of iNOS in SHR was attenuated by antihypertensive therapy, suggesting that the abnormal expression of iNOS is associated with hypertension [5].

Psychiatry related information on Nos2

  • Food deprivation totally attenuated both iNOS expression and lesion formation in response to indomethacin [6].
  • ALA plays an important role in treatment of erectile dysfunction by decreasing iNOS and increasing other isoforms of NOS [7].
  • Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD) [8].
  • This study provides the first evidence that heroin induces an alteration of iNOS expression, and suggests that a reduction in nitric oxide production may be involved in the increased incidence of infectious diseases amongst heroin users [9].

High impact information on Nos2

  • Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS) [10].
  • Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis [10].
  • The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis [10].
  • In contrast, IL-1 beta induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facs-purified beta cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified beta cells [11].
  • Treatment of rat islets with a combination of tumor necrosis factor (TNF) and lipopolysaccharide (LPS), conditions known to activate macrophages, stimulate the expression of iNOS and the formation of nitrite [11].

Chemical compound and disease context of Nos2


Biological context of Nos2


Anatomical context of Nos2

  • Identification of cis-regulatory regions necessary for robust Nos2 promoter activity in glial cells: indirect role for NF-kappaB [19].
  • This was addressed by measuring Nos1, Nos2, and Nos3 mRNA in the kidney, adrenal gland, heart, and hypothalamus of 16 ACTH-treated and 16 vehicle-treated rats as well as in 10 corticosterone-treated and 10 control rats [20].
  • Ligation of the common hepatic bile duct, which induces periportal-based liver injury, stimulated iNOS mRNA in lipocytes [21].
  • It remained unclear which specific inflammatory cytokines in this medium contribute to the induction of iNOS activity in myocytes and whether induction of iNOS would result in an obligatory decline in contractile function [22].
  • In the aging aortas, the expression of both eNOS and iNOS isoforms was enhanced [23].

Associations of Nos2 with chemical compounds

  • Northern analysis showed that homocysteine treatment increased steady-state Nos2 mRNA levels by 61% at 6 hr as compared with controls, an effect that was not caused by changes in message stability [1].
  • In conclusion, we have shown for the first time that the physiological components of glucocorticoid action (ACTH and corticosterone) when given chronically in vivo reduce Nos2 and Nos3 expression in the kidney [20].
  • Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats [24].
  • Transforming growth factor-beta 1 decreased IFN-gamma/TNF-alpha--stimulated iNOS mRNA and nitrite [21].
  • However, only IL-1 receptor antagonist and not an anti-rat TNF-alpha antiserum diminished the extent of iNOS induction in myocytes exposed to this medium and prevented a decline in contractile responsiveness to isoproterenol [22].

Physical interactions of Nos2

  • Here we show that cNOS isoforms contain a unique polypeptide insert in their FMN binding domains which is not shared with iNOS or other related flavoproteins [25].
  • The results suggest that the anti-inflammatory properties of oxyresveratrol might be correlated with inhibition of the iNOS expression through down-regulation of NF-kappaB binding activity and significant inhibition of COX-2 activity [26].

Co-localisations of Nos2

  • Increased nitrotyrosine was accompanied by an elevation of the apoptotic index in the old rats (SON: 11.01 +/- 3.33 vs. 0.57 +/- 0.50, p < 0.001; PVN: 3.08 +/- 1.12 vs. 0.42 +/- 0.32; POA: 6.60 +/- 1.93 vs. 0.18 +/- 0.17, p < 0.01; ARC: 0.001 +/- 0.0001 vs. 4.33 +/- 2.33). iNOS staining co-localized with GnRH and oxytocin staining [27].

Regulatory relationships of Nos2

  • Here we found that eNOS mRNA is induced in the rat brain by intraperitoneal injection of LPS of a smaller amount than that required for induction of iNOS mRNA [28].
  • However, when added together with interleukin-1beta, angiotensin II, through activation of the AT(1) receptor, inhibited iNOS expression and enhanced VCAM-1 expression induced by the cytokine [29].
  • The iNOS inhibitor aminoguanidine significantly suppressed the induction of HO-1 [30].
  • As demonstrated by reverse transcriptase-PCR analysis, IL-1 beta-stimulated NO generation was accompanied by a time-dependent increase in messenger RNA levels for iNOS and GTP-cyclohydrolase (GTPCH), the rate-limiting step for de novo tetrahydrobiopterin (BH4) biosynthesis [31].
  • The results demonstrate that ET-1 can strongly inhibit cytokine induction of iNOS and formation of NO in cultured MCs, and that this action is mediated via the ETA receptor [32].

Other interactions of Nos2

  • These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition [24].
  • Intraperitoneal administration of IFN-gamma, TNF-alpha, and LPS led to rapid induction of iNOS mRNA in lipocytes, confirming in vivo the culture findings [21].
  • Transforming growth factor-beta (TGF-beta) decreases iNOS activity, protein content, and mRNA abundance in IL-1 beta- and IFN-gamma-pretreated CMEC [33].
  • Pulmonary intravascular macrophages also accumulated after CBDL and expressed HO-1 and iNOS at 3 weeks [34].
  • Although no consensus PPAR gamma:RXR-responsive element in the promoter regions of the inducible isoform of nitric oxide synthase (iNOS) and TNF-alpha genes was found, PPAR gamma:RXR may interfere with NF-kappa B and AP-1 transcriptional activity [35].

Analytical, diagnostic and therapeutic context of Nos2


  1. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2. Welch, G.N., Upchurch, G.R., Farivar, R.S., Pigazzi, A., Vu, K., Brecher, P., Keaney, J.F., Loscalzo, J. Proc. Assoc. Am. Physicians (1998) [Pubmed]
  2. Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Szabó, C., Zingarelli, B., Salzman, A.L. Circ. Res. (1996) [Pubmed]
  3. Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats. Wang, W.W., Smith, D.L., Zucker, S.D. Hepatology (2004) [Pubmed]
  4. Expression and localization of inducible nitric oxide synthase in anti-Thy-1 glomerulonephritis. Goto, S., Yamamoto, T., Feng, L., Yaoita, E., Hirose, S., Fujinaka, H., Kawasaki, K., Hattori, R., Yui, Y., Wilson, C.B. Am. J. Pathol. (1995) [Pubmed]
  5. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Chou, T.C., Yen, M.H., Li, C.Y., Ding, Y.A. Hypertension (1998) [Pubmed]
  6. Factors Involved in Upregulation of Inducible Nitric Oxide Synthase in Rat Small Intestine Following Administration of Nonsteroidal Anti-inflammatory Drugs. Takeuchi, K., Yokota, A., Tanaka, A., Takahira, Y. Dig. Dis. Sci. (2006) [Pubmed]
  7. The effects of alpha-lipoic acid on nitric oxide synthetase dispersion in penile function in streptozotocin-induced diabetic rats. Hurdag, C., Ozkara, H., Citci, S., Uyaner, I., Demirci, C. International journal of tissue reactions. (2005) [Pubmed]
  8. Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. Heneka, M.T., Klockgether, T., Feinstein, D.L. J. Neurosci. (2000) [Pubmed]
  9. Heroin modulates the expression of inducible nitric oxide synthase. Lysle, D.T., How, T. Immunopharmacology (2000) [Pubmed]
  10. Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Wong, M.L., Rettori, V., al-Shekhlee, A., Bongiorno, P.B., Canteros, G., McCann, S.M., Gold, P.W., Licinio, J. Nat. Med. (1996) [Pubmed]
  11. Intraislet release of interleukin 1 inhibits beta cell function by inducing beta cell expression of inducible nitric oxide synthase. Corbett, J.A., McDaniel, M.L. J. Exp. Med. (1995) [Pubmed]
  12. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Rabiller, A., Nunes, H., Lebrec, D., Tazi, K.A., Wartski, M., Dulmet, E., Libert, J.M., Mougeot, C., Moreau, R., Mazmanian, M., Humbert, M., Hervé, P. Am. J. Respir. Crit. Care Med. (2002) [Pubmed]
  13. Chronic liver injury alters basal and stimulated nitric oxide production and 3H-thymidine incorporation in cultured sinusoidal endothelial cells from rats. Petermann, H., Vogl, S., Schulze, E., Dargel, R. J. Hepatol. (1999) [Pubmed]
  14. An octamer motif is required for activation of the inducible nitric oxide synthase promoter in pancreatic beta-cells. Darville, M.I., Terryn, S., Eizirik, D.L. Endocrinology (2004) [Pubmed]
  15. Selective cannabinoid CB1 receptor-mediated inhibition of inducible nitric oxide synthase protein expression in C6 rat glioma cells. Esposito, G., Izzo, A.A., Di Rosa, M., Iuvone, T. J. Neurochem. (2001) [Pubmed]
  16. Expression of nitric oxide synthases and GTP cyclohydrolase I in the ventilatory and limb muscles during endotoxemia. Hussain, S.N., Giaid, A., El Dawiri, Q., Sakkal, D., Hattori, R., Guo, Y. Am. J. Respir. Cell Mol. Biol. (1997) [Pubmed]
  17. Locus for the inducible, but not a constitutive, nitric oxide synthase cosegregates with blood pressure in the Dahl salt-sensitive rat. Deng, A.Y., Rapp, J.P. J. Clin. Invest. (1995) [Pubmed]
  18. Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells. Larsen, L., Størling, J., Darville, M., Eizirik, D.L., Bonny, C., Billestrup, N., Mandrup-Poulsen, T. Diabetologia (2005) [Pubmed]
  19. Identification of cis-regulatory regions necessary for robust Nos2 promoter activity in glial cells: indirect role for NF-kappaB. Sanchez, A.C., Davis, R.L., Syapin, P.J. J. Neurochem. (2003) [Pubmed]
  20. Decreased renal expression of nitric oxide synthase isoforms in adrenocorticotropin-induced and corticosterone-induced hypertension. Lou , Y.K., Wen, C., Li, M., Adams, D.J., Wang , M.X., Yang, F., Morris, B.J., Whitworth, J.A. Hypertension (2001) [Pubmed]
  21. Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. Rockey, D.C., Chung, J.J. J. Clin. Invest. (1995) [Pubmed]
  22. Induction of nitric oxide synthase activity by cytokines in ventricular myocytes is necessary but not sufficient to decrease contractile responsiveness to beta-adrenergic agonists. Ungureanu-Longrois, D., Balligand, J.L., Simmons, W.W., Okada, I., Kobzik, L., Lowenstein, C.J., Kunkel, S.L., Michel, T., Kelly, R.A., Smith, T.W. Circ. Res. (1995) [Pubmed]
  23. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Cernadas, M.R., Sánchez de Miguel, L., García-Durán, M., González-Fernández, F., Millás, I., Montón, M., Rodrigo, J., Rico, L., Fernández, P., de Frutos, T., Rodríguez-Feo, J.A., Guerra, J., Caramelo, C., Casado, S., López-Farré, n.u.l.l. Circ. Res. (1998) [Pubmed]
  24. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. Schwartz, D., Mendonca, M., Schwartz, I., Xia, Y., Satriano, J., Wilson, C.B., Blantz, R.C. J. Clin. Invest. (1997) [Pubmed]
  25. An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase. Salerno, J.C., Harris, D.E., Irizarry, K., Patel, B., Morales, A.J., Smith, S.M., Martasek, P., Roman, L.J., Masters, B.S., Jones, C.L., Weissman, B.A., Lane, P., Liu, Q., Gross, S.S. J. Biol. Chem. (1997) [Pubmed]
  26. In-vitro and in-vivo anti-inflammatory effect of oxyresveratrol from Morus alba L. Chung, K.O., Kim, B.Y., Lee, M.H., Kim, Y.R., Chung, H.Y., Park, J.H., Moon, J.O. J. Pharm. Pharmacol. (2003) [Pubmed]
  27. Aging-related increased expression of inducible nitric oxide synthase and cytotoxicity markers in rat hypothalamic regions associated with male reproductive function. Ferrini, M., Wang, C., Swerdloff, R.S., Sinha Hikim, A.P., Rajfer, J., Gonzalez-Cadavid, N.F. Neuroendocrinology (2001) [Pubmed]
  28. Induction of endothelial nitric-oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment. Iwase, K., Miyanaka, K., Shimizu, A., Nagasaki, A., Gotoh, T., Mori, M., Takiguchi, M. J. Biol. Chem. (2000) [Pubmed]
  29. Angiotensin II differentially regulates interleukin-1-beta-inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) expression: role of p38 MAPK. Jiang, B., Xu, S., Hou, X., Pimentel, D.R., Cohen, R.A. J. Biol. Chem. (2004) [Pubmed]
  30. Oxidative stress induces vascular heme oxygenase-1 expression in ovariectomized rats. Lee, Y.M., Cheng, P.Y., Hong, S.F., Chen, S.Y., Lam, K.K., Sheu, J.R., Yen, M.H. Free Radic. Biol. Med. (2005) [Pubmed]
  31. Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 beta-stimulated nitric oxide synthase activity in granulosa cells. Tabraue, C., Diaz Peñate, R., Gallardo, G., Hernandez, I., Quintana, J., Lopez Blanco, F., Gonzalez Reyes, J., Fanjul, L.F., Ruiz de Galarreta, C.M. Endocrinology (1997) [Pubmed]
  32. Endothelin-1 inhibits cytokine-stimulated transcription of inducible nitric oxide synthase in glomerular mesangial cells. Beck, K.F., Mohaupt, M.G., Sterzel, R.B. Kidney Int. (1995) [Pubmed]
  33. Contractile responsiveness of ventricular myocytes to isoproterenol is regulated by induction of nitric oxide synthase activity in cardiac microvascular endothelial cells in heterotypic primary culture. Ungureanu-Longrois, D., Balligand, J.L., Okada, I., Simmons, W.W., Kobzik, L., Lowenstein, C.J., Kunkel, S.L., Michel, T., Kelly, R.A., Smith, T.W. Circ. Res. (1995) [Pubmed]
  34. The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat. Ling, Y., Zhang, J., Luo, B., Song, D., Liu, L., Tang, L., Stockard, C.R., Grizzle, W.E., Ku, D.D., Fallon, M.B. Hepatology (2004) [Pubmed]
  35. Activation of retinoic X receptor and peroxisome proliferator-activated receptor-gamma inhibits nitric oxide and tumor necrosis factor-alpha production in rat Kupffer cells. Uchimura, K., Nakamuta, M., Enjoji, M., Irie, T., Sugimoto, R., Muta, T., Iwamoto, H., Nawata, H. Hepatology (2001) [Pubmed]
  36. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. Balligand, J.L., Ungureanu-Longrois, D., Simmons, W.W., Pimental, D., Malinski, T.A., Kapturczak, M., Taha, Z., Lowenstein, C.J., Davidoff, A.J., Kelly, R.A. J. Biol. Chem. (1994) [Pubmed]
  37. Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts. Akyürek, L.M., Fellström, B.C., Yan, Z.Q., Hansson, G.K., Funa, K., Larsson, E. Am. J. Pathol. (1996) [Pubmed]
  38. Interleukin-1beta regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signaling pathways in cardiac myocytes. LaPointe, M.C., Isenović, E. Hypertension (1999) [Pubmed]
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