Advertisement

Role of iNOS in Insulin Resistance and Endothelial Dysfunction

  • Hobby Aggarwal
  • Babu Nageswararao Kanuri
  • Madhu Dikshit
Chapter

Abstract

Nitric oxide (NO) is an important gaseous signaling molecule with diverse roles in various physiological processes like maintenance of vascular tone, regulation of metabolism, cell apoptosis etc. NO synthesis in the body is regulated by nitric oxide synthase (NOS); primarily by Ca2+ dependent endothelial and neuronal (eNOS and nNOS), and Ca2+ independent inducible (iNOS) isoforms. Insulin resistance (IR), a critical component in the pathophysiology of lifestyle diseases such as obesity and Type 2 diabetes is characterized by hyperglycemia, dyslipidemia and is also linked to altered gut microbiome. Endothelial dysfunction in obesity and diabetes enhance the risk of cardiovascular complications such as hypertension, atherosclerosis, myocardial infarction, and cerebral stroke. iNOS, which produces high and sustained levels of NO under pathophysiological stimuli is implicated to have deleterious effects on cardiovascular system. During insulin resistant states and its associated complications, iNOS participates in deregulating tissue metabolic processes via imbalance in homeostasis of glucose and lipids as well as endothelial dysfunction through local and systemic inflammatory milieu. This is majorly a resultant of increased nitrosative stress (due to ONOO release formed by combination of NO and O2) which impacts the functions of various proteins involved in maintaining the metabolism and vascular homeostasis by S-glutathionylation of cysteine and/or nitration of tyrosine residues of crucial proteins. Decreased availability of tissue NO in these diseased conditions has opened a new arena of therapeutics focusing on increasing the NO bioavailability via administration of NO precursors such as arginine, nitrite and cell permeable tetrahydrobiopterin analogs on one hand or through a search for selective iNOS inhibitors on the other. This chapter focuses on the role of iNOS in insulin resistance and endothelial functionality through its modulatory effects on tissue metabolism and inflammatory cytokines.

References

  1. 1.
    Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ginsberg HN (2000) Insulin resistance and cardiovascular disease. J Clin Invest 106:453–458CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bloomgarden ZT (2007) Insulin resistance, dyslipidemia, and cardiovascular disease. Diabetes Care 30:2164–2170CrossRefPubMedGoogle Scholar
  4. 4.
    Bhupathiraju SN, Hu FB (2016) Epidemiology of obesity and diabetes and their cardiovascular complications. Circ Res 118:1723–1735CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    International Diabetes Federation (2017) IDF DIABETES ATLAS Eighth edition. At <file:///C:/Users/HOBBY/Downloads/IDF_DA_8e-EN-final.pdf>Google Scholar
  6. 6.
    Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2:820–832CrossRefPubMedGoogle Scholar
  7. 7.
    Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A (2009) Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89:27–71CrossRefPubMedGoogle Scholar
  8. 8.
    Kanuri BN et al (2018) Glucose and lipid metabolism alterations in liver and adipose tissue pre-dispose p47 phox knockout mice to systemic insulin resistance. Free Radic Res 52:568–582CrossRefPubMedGoogle Scholar
  9. 9.
    Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948CrossRefPubMedGoogle Scholar
  10. 10.
    Berdichevsky A, Guarente L, Bose A (2010) Acute oxidative stress can reverse insulin resistance by inactivation of cytoplasmic JNK. J Biol Chem 285:21581–21589CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kelm M (1999) Nitric oxide metabolism and breakdown. Biochim Biophys Acta Bioenerg 1411:273–289CrossRefGoogle Scholar
  12. 12.
    Levine AB, Punihaole D, Levine TB (2012) Characterization of the role of nitric oxide and its clinical applications. Cardiology 122:55–68CrossRefPubMedGoogle Scholar
  13. 13.
    Pautz A et al (2010) Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 23:75–93CrossRefPubMedGoogle Scholar
  14. 14.
    Tzeng E, Billiar TR, Robbins PD, Loftus M, Stuehr DJ (1995) Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line: H4B promotes assembly of enzyme subunits into an active dimer. Proc Natl Acad Sci U S A 92:11771–11775CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mori M, Gotoh T (2000) Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun 275:715–719CrossRefPubMedGoogle Scholar
  16. 16.
    Saluja R et al (2011) Molecular and biochemical characterization of nitric oxide synthase isoforms and their intracellular distribution in human peripheral blood mononuclear cells. Biochim Biophys Acta, Mol Cell Res 1813:1700–1707CrossRefPubMedGoogle Scholar
  17. 17.
    Villanueva C, Giulivi C (2007) Subcellular and cellular locations of nitric-oxide synthase isoforms as determinants of health and disease. Free Radic Biol Med.  https://doi.org/10.1016/j.freeradbiomed.2010.04.004
  18. 18.
    Rana M et al (2015) Turmerone enriched standardized Curcuma longa extract alleviates LPS induced inflammation and cytokine production by regulating TLR4–IRAK1–ROS–MAPK–NFκB axis. J Funct Foods 16:152–163CrossRefGoogle Scholar
  19. 19.
    Charbonneau A, Marette A (2010) Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice potential role of tyrosine nitration of insulin signaling proteins. Diabetes 59:861–871CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918CrossRefPubMedGoogle Scholar
  21. 21.
    Michel T, Feron O (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100:2146–2152CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kim Y-M, Bergonia H, Lancaster JR (1995) Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett 374:228–232CrossRefPubMedGoogle Scholar
  23. 23.
    Kim F et al (2008) Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol 28:1982–1988CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gruber H-J et al (2008) Obesity reduces the bioavailability of nitric oxide in juveniles. Int J Obes 32:826–831CrossRefGoogle Scholar
  25. 25.
    Honing MLH, Morrison PJ, Banga JD, Stroes ESG, Rabelink TJ (1998) Nitric oxide availability in diabetes mellitus. Diabetes/Metab Rev 14:241–249CrossRefGoogle Scholar
  26. 26.
    Perreault M, Marette A (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7:1138–1143CrossRefPubMedGoogle Scholar
  27. 27.
    Dallaire P et al (2008) Obese mice lacking inducible nitric oxide synthase are sensitized to the metabolic actions of peroxisome proliferator-activated receptor-gamma agonism. Diabetes 57:1999–2011CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sudar E et al (2011) Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. J Physiol Biochem 67:195–204CrossRefPubMedGoogle Scholar
  29. 29.
    Duncan ER et al (2008) Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes 57:3307–3314CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kanuri BN et al (2017) Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance. Sci Rep 7:41009CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Eriksson JW (2007) Metabolic stress in insulin’s target cells leads to ROS accumulation – a hypothetical common pathway causing insulin resistance. FEBS Lett 581:3734–3742CrossRefPubMedGoogle Scholar
  32. 32.
    Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806CrossRefPubMedGoogle Scholar
  33. 33.
    Bray GA, Popkin BM (1998) Dietary fat intake does affect obesity! Am J Clin Nutr 68:1157–1173CrossRefPubMedGoogle Scholar
  34. 34.
    Liu L et al (2007) Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 117:1679–1689CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Liu Z et al (2015) High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoS One 10:e0128274CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269:4705–4708PubMedGoogle Scholar
  37. 37.
    Shimabukuro M, Ohneda M, Lee Y, Unger RH (1997) Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 100:290–295CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Noronha BT, Li J-M, Wheatcroft SB, Shah AM, Kearney MT (2005) Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity. Diabetes 54:1082–1089CrossRefPubMedGoogle Scholar
  39. 39.
    Fujimoto M et al (2005) A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. Diabetes 54:1340–1348CrossRefPubMedGoogle Scholar
  40. 40.
    Lumeng CN, DeYoung SM, Bodzin JL, Saltiel AR (2006) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23CrossRefGoogle Scholar
  41. 41.
    Tannous M et al (1999) Evidence for iNOS-dependent peroxynitrite production in diabetic platelets. Diabetologia 42:539–544CrossRefPubMedGoogle Scholar
  42. 42.
    Engeli S et al (2004) Regulation of the nitric oxide system in human adipose tissue. J Lipid Res 45:1640–1648CrossRefPubMedGoogle Scholar
  43. 43.
    Meininger CJ et al (2004) GTP cyclohydrolase I gene transfer reverses tetrahydrobiopterin deficiency and increases nitric oxide synthesis in endothelial cells and isolated vessels from diabetic rats. FASEB J 18:1900–1902CrossRefPubMedGoogle Scholar
  44. 44.
    Choi JW et al (2001) Increases in nitric oxide concentrations correlate strongly with body fat in obese humans. Clin Chem 47:1106–1109PubMedGoogle Scholar
  45. 45.
    Mercuri F et al (2001) Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44:834–838CrossRefPubMedGoogle Scholar
  46. 46.
    Torres SH, De Sanctis JB, de L Briceño M, Hernández N, Finol HJ (2004) Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients. J Endocrinol 181:419–427CrossRefPubMedGoogle Scholar
  47. 47.
    Frisbee JC, Maier KG, Stepp DW (2002) Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats. Am J Physiol Circ Physiol 283:H2160–H2168CrossRefGoogle Scholar
  48. 48.
    House LM et al (2015) Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance. Cardiovasc Diabetol 14:56CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sugita H et al (2005) Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells. J Biol Chem 280:14203–14211CrossRefPubMedGoogle Scholar
  50. 50.
    Uehara T et al (2006) S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513–517CrossRefPubMedGoogle Scholar
  51. 51.
    Jeon MJ et al (2012) Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3L1 adipocytes. Exp Mol Med 44:562CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Zanotto TM et al (2017) Blocking iNOS and endoplasmic reticulum stress synergistically improves insulin resistance in mice. Mol Metab 6:206–218CrossRefPubMedGoogle Scholar
  53. 53.
    Pilon G et al (2010) Endotoxin mediated-iNOS induction causes insulin resistance via ONOO− induced tyrosine nitration of IRS-1 in skeletal muscle. PLoS One 5:e15912CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 87:91. At <https://www.scopus.com/record/display.uri?eid=2-s2.0-0027459878&origin=inward&txGid=85277588BE5D03F4BA6E74E1DC1E1918.wsnAw8kcdt7IPYLO0V48gA%253a2>
  55. 55.
    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM (1994) Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 91:4854–4858CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Shinozaki S et al (2011) Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. J Biol Chem 286:34959–34975CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Spruss A, Kanuri G, Uebel K, Bischoff SC, Bergheim I (2011) Role of the inducible nitric oxide synthase in the onset of fructose-induced steatosis in mice. Antioxid Redox Signal 14:2121–2135CrossRefPubMedGoogle Scholar
  58. 58.
    Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55:S9–S15CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Turinsky J, O’Sullivan DM, Bayly BP (1990) 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem 265:16880–16885PubMedGoogle Scholar
  60. 60.
    Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E (2005) Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. J Biol Chem 280:34786–34795CrossRefPubMedGoogle Scholar
  61. 61.
    Khedara A, Goto T, Morishima M, Kayashita J, Kato N (1999) Elevated body fat in rats by the dietary nitric oxide synthase inhibitor, L -N ω nitroarginine. Biosci Biotechnol Biochem 63:698–702CrossRefPubMedGoogle Scholar
  62. 62.
    Cha H-N et al (2010) Lack of inducible nitric oxide synthase does not prevent aging-associated insulin resistance. Exp Gerontol 45:711–718CrossRefPubMedGoogle Scholar
  63. 63.
    Cani PD, Delzenne NM (2009) The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15:1546–1558CrossRefPubMedGoogle Scholar
  64. 64.
    Singh A et al (2016) The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-1β transcription and processing in monocytes. Cell Mol Immunol 13:745–763CrossRefPubMedGoogle Scholar
  65. 65.
    Sugita H et al (2002) Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance. Am J Physiol Metab 282:E386–E394Google Scholar
  66. 66.
    Ropelle ER et al (2013) Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Diabetes 62:466–470CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ko S-H et al (2008) Inducible nitric oxide synthase-nitric oxide plays an important role in acute and severe hypoxic injury to pancreatic beta cells. Transplantation 85:323–330CrossRefPubMedGoogle Scholar
  68. 68.
    Tanioka T et al (2011) Inducible nitric-oxide synthase and nitric oxide donor decrease insulin receptor substrate-2 protein expression by promoting proteasome-dependent degradation in pancreatic β-cells. J Biol Chem 286:29388–29396CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Jang JE et al (2016) Nitric oxide produced by macrophages inhibits adipocyte differentiation and promotes profibrogenic responses in preadipocytes to induce adipose tissue fibrosis. Diabetes 65:2516–2528CrossRefPubMedGoogle Scholar
  70. 70.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lu M et al (2010) Inducible nitric oxide synthase deficiency in myeloid cells does not prevent diet-induced insulin resistance. Mol Endocrinol 24:1413–1422CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Epstein FH, Vane JR, Änggård EE, Botting RM (1990) Regulatory functions of the vascular endothelium. N Engl J Med 323:27–36CrossRefGoogle Scholar
  73. 73.
    Furchgott RF (1999) Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep 19:235–251CrossRefPubMedGoogle Scholar
  74. 74.
    Miao C-Y, Li Z-Y (2012) The role of perivascular adipose tissue in vascular smooth muscle cell growth. Br J Pharmacol 165:643–658CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Muniyappa R, Montagnani M, Koh KK, Quon MJ (2007) Cardiovascular actions of insulin. Endocr Rev 28:463–491CrossRefPubMedGoogle Scholar
  76. 76.
    Raghavan SA, Dikshit M (2004) Vascular regulation by the l-arginine metabolites, nitric oxide and agmatine. Pharmacol Res 49:397–414CrossRefPubMedGoogle Scholar
  77. 77.
    Kearney MT, Duncan ER, Kahn M, Wheatcroft SB (2008) Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Exp Physiol 93:158–163CrossRefPubMedGoogle Scholar
  78. 78.
    Soskić SS et al (2011) Regulation of inducible nitric oxide synthase (iNOS) and its potential role in insulin resistance, diabetes and heart failure. Open Cardiovasc Med J 5:153–163CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ (2005) Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group… – PubMed – NCBI. J Hypertens 23:7–17CrossRefPubMedGoogle Scholar
  80. 80.
    Cai H, Harrison DG (2011) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. At <http://circres.ahajournals.org/content/87/10/. http://www.lww.com/reprints. http://circres.ahajournals.org/Downloadedfrom>
  81. 81.
    Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis. JAMA 287:2570CrossRefGoogle Scholar
  82. 82.
    Priya P, Jitendra K, Sanjay R, Kanuri BN, Sachin K, Kumaravelu J, Dikshit (2017) Inducible nitric oxide synthase deficiency preserves vascular function despite systemic insulin resistance in diet-induced mouse model of obesity. In Molecular medicines for lifestyle diseases: emerging targets and approaches, vol 82Google Scholar
  83. 83.
    Cersosimo E, DeFronzo RA (2006) Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 22:423–436CrossRefPubMedGoogle Scholar
  84. 84.
    Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625CrossRefGoogle Scholar
  85. 85.
    Yogo K et al (2000) Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 20:E96–E100CrossRefPubMedGoogle Scholar
  86. 86.
    Koglin J, Glysing-Jensen T, Mudgett JS, Russell ME (1998) Exacerbated transplant arteriosclerosis in inducible nitric oxide-deficient mice. Circulation 97:2059–2065CrossRefPubMedGoogle Scholar
  87. 87.
    Hansson GK et al (1994) Arterial smooth muscle cells express nitric oxide synthase in response to endothelial injury. J Exp Med 180:733–738CrossRefPubMedGoogle Scholar
  88. 88.
    Kibbe M, Billiar T, Tzeng E (1999) Inducible nitric oxide synthase and vascular injury. Cardiovasc Res 43:650–657CrossRefPubMedGoogle Scholar
  89. 89.
    Miyoshi T et al (2006) Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice. Life Sci 79:525–531CrossRefPubMedGoogle Scholar
  90. 90.
    Chyu KY et al (1999) Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res 85:1192–1198CrossRefPubMedGoogle Scholar
  91. 91.
    Kuhlencordt PJ, Chen J, Han F, Astern J, Huang PL (2001) Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 103:3099–3104CrossRefPubMedGoogle Scholar
  92. 92.
    Tsuchiya K et al (2012) FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab 15:372–381CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Dimmeler S et al (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605CrossRefPubMedGoogle Scholar
  94. 94.
    Hsueh WA, Law RE (1999) Insulin signaling in the arterial wall. Am J Cardiol 84:21–24CrossRefGoogle Scholar
  95. 95.
    Marasciulo FL, Montagnani M, Potenza MA (2006) Endothelin-1: the yin and yang on vascular function. Curr Med Chem 13:1655–1665CrossRefPubMedGoogle Scholar
  96. 96.
    Montagnani M et al (2002) Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 277:1794–1799CrossRefGoogle Scholar
  97. 97.
    Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605CrossRefGoogle Scholar
  98. 98.
    Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436–2443CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A (2016) Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediat Inflamm 2016:3634948CrossRefGoogle Scholar
  100. 100.
    Kaiser N et al (1993) Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes 42:80–89CrossRefPubMedGoogle Scholar
  101. 101.
    Pieper GM, Riaz-ul-Haq (1997) Activation of nuclear factor-kappaB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. J Cardiovasc Pharmacol 30:528–532CrossRefPubMedGoogle Scholar
  102. 102.
    Williams B, Gallacher B, Patel H, Orme C (1997) Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 46:1497–1503CrossRefPubMedGoogle Scholar
  103. 103.
    Li H, Li H, Bao Y, Zhang X, Yu Y (2011) Free fatty acids induce endothelial dysfunction and activate protein kinase C and nuclear factor-κB pathway in rat aorta. Int J Cardiol 152:218–224CrossRefPubMedGoogle Scholar
  104. 104.
    Inoguchi T et al (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945CrossRefGoogle Scholar
  105. 105.
    Mathew M, Tay E, Cusi K (2010) Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol 9:9CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Baker RG, Hayden MS, Ghosh S (2011) NF-κB, inflammation, and metabolic disease. Cell Metab 13:11–22CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Paulus WJ, Frantz S, Kelly RA (2001) Nitric oxide and cardiac contractility in human heart failure: time for reappraisal. Circulation 104:2260–2262CrossRefPubMedGoogle Scholar
  108. 108.
    Haywood GA et al (1996) Expression of inducible nitric oxide synthase in human heart failure. Circulation 93:1087–1094CrossRefPubMedGoogle Scholar
  109. 109.
    Heusch P et al (2010) Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S -nitrosylation. Am J Physiol Circ Physiol 299:H446–H453CrossRefGoogle Scholar
  110. 110.
    Vejlstrup NG et al (1998) Inducible nitric oxide synthase (iNOS) in the human heart: expression and localization in congestive heart failure. J Mol Cell Cardiol 30:1215–1223CrossRefPubMedGoogle Scholar
  111. 111.
    Zhang C et al (2005) TNF- contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 26:475–480CrossRefPubMedGoogle Scholar
  112. 112.
    Drexler H, Hornig B (1999) Endothelial dysfunction in human disease. J Mol Cell Cardiol 31:51–60CrossRefPubMedGoogle Scholar
  113. 113.
    Liu Y-H et al (2005) Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289:H2616–H2623CrossRefPubMedGoogle Scholar
  114. 114.
    Xi L, Jarrett NC, Hess ML, Kukreja RC (1999) Myocardial ischemia/reperfusion injury in the inducible nitric oxide synthase knockout mice. Life Sci 65:935–945CrossRefPubMedGoogle Scholar
  115. 115.
    Sam F et al (2001) Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res 89:351–356CrossRefPubMedGoogle Scholar
  116. 116.
    Rösen P, Ballhausen T, Stockklauser K (1996) Impairment of endothelium dependent relaxation in the diabetic rat heart: mechanisms and implications. Diabetes Res Clin Pract 31:S143–S155CrossRefPubMedGoogle Scholar
  117. 117.
    Nitenberg A et al (1993) Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 42:1017–1025CrossRefPubMedGoogle Scholar
  118. 118.
    Mungrue IN et al (2002) Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109:735–743CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Guo Y et al (1999) The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci U S A 96:11507–11512CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Prakash P et al (2011) Atorvastatin protects against ischemia-reperfusion injury in fructose-induced insulin resistant rats. Cardiovasc Drugs Ther 25:285–297CrossRefPubMedGoogle Scholar
  121. 121.
    Lee JK, Borhani M, Ennis TL, Upchurch GR, Thompson RW (2001) Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 21:1393–1401CrossRefPubMedGoogle Scholar
  122. 122.
    Prakash R et al (2012) Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes 61:1533–1542CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC (2012) Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 12:148–158CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Last D et al (2007) Global and regional effects of type 2 diabetes on brain tissue volumes and cerebral vasoreactivity. Diabetes Care 30:1193–1199CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Calvert JW, Lefer DJ (2010) Clinical translation of nitrite therapy for cardiovascular diseases. Nitric Oxide 22:91–97CrossRefPubMedGoogle Scholar
  127. 127.
    Shukla A, Dikshit M, Srimal RC (1995) Nitric oxide modulates blood-brain barrier permeability during infections with an inactivated bacterium. Neuroreport 6:1629–1632CrossRefPubMedGoogle Scholar
  128. 128.
    Faraci FM, Brian JE (1994) Nitric oxide and the cerebral circulation. Stroke 25:692–703CrossRefPubMedGoogle Scholar
  129. 129.
    Zheng Z, Yenari MA (2004) Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 26:884–892CrossRefPubMedGoogle Scholar
  130. 130.
    Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136CrossRefPubMedGoogle Scholar
  131. 131.
    Rosenberg GA (1999) Ischemic brain edema. Prog Cardiovasc Dis 42:209–216CrossRefPubMedGoogle Scholar
  132. 132.
    Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397CrossRefPubMedGoogle Scholar
  133. 133.
    Endoh M, Maiese K, Wagner J (1994) Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res 651:92–100CrossRefPubMedGoogle Scholar
  134. 134.
    Iadecola C, Zhang F, Xu S, Casey R, Ross ME (1995) Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:378–384CrossRefPubMedGoogle Scholar
  135. 135.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14CrossRefPubMedGoogle Scholar
  136. 136.
    Iadecola C, Zhang F, Xu X (1995) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol Integr Comp Physiol 268:R286–R292CrossRefGoogle Scholar
  137. 137.
    Zhao X, Haensel C, Araki E, Ross ME, Iadecola C (2000) Gene-dosing effect and persistence of reduction in ischemic brain injury in mice lacking inducible nitric oxide synthase. Brain Res 872:215–218CrossRefPubMedGoogle Scholar
  138. 138.
    Członkowska A, Cyrta B, Korlak J (1979) Immunological observations on patients with acute cerebral vascular disease. J Neurol Sci 43:455–464CrossRefPubMedGoogle Scholar
  139. 139.
    Prass K et al (2003) Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1–like immunostimulation. J Exp Med 198:725–736CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Korhonen P et al (2015) Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation. Brain Behav Immun 49:322–336CrossRefPubMedGoogle Scholar
  141. 141.
    Benakis C et al (2016) Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med 22:516–523CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Hum PD et al (2007) T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 27:1798–1805CrossRefGoogle Scholar
  143. 143.
    Gan Y et al (2014) Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci 111:2704–2709CrossRefPubMedGoogle Scholar
  144. 144.
    Liesz A et al (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–199CrossRefPubMedGoogle Scholar
  145. 145.
    Kim J, Montagnani M, Koh KK, Quon MJ (2006) Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113:1888–1904CrossRefPubMedGoogle Scholar
  146. 146.
    Jain M, Barthwal MK, Haq W, Katti SB, Dikshit M (2012) Synthesis and pharmacological evaluation of novel arginine analogs as potential inhibitors of acetylcholine-induced relaxation in rat thoracic aortic rings. Chem Biol Drug Des 79:459–469CrossRefPubMedGoogle Scholar
  147. 147.
    Jun T, Wennmalm A (1994) NO-dependent and -independent elevation of plasma levels of insulin and glucose in rats by L-arginine. Br J Pharmacol 113:345–348CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Piatti PM et al (2001) Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 24:875–880CrossRefPubMedGoogle Scholar
  149. 149.
    Bogdanski P et al (2012) Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity. At <https://www.europeanreview.org/wp/wp-content/uploads/1081.pdf>
  150. 150.
    Lucotti P et al (2006) Beneficial effects of a long-term oral l -arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. Am J Physiol Metab 291:E906–E912Google Scholar
  151. 151.
    La Mura V et al (2014) Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase. J Hepatol 61:1321–1327CrossRefPubMedGoogle Scholar
  152. 152.
    Darley-Usmar V, Wiseman H, Halliwell B (1995) Nitric oxide and oxygen radicals: a question of balance. FEBS Lett 369:131–135CrossRefPubMedGoogle Scholar
  153. 153.
    Wei C-L, Hon W-M, Lee K-H, Khoo H-E (2005) Chronic administration of aminoguanidine reduces vascular nitric oxide production and attenuates liver damage in bile duct-ligated rats. Liver Int 25:647–656CrossRefPubMedGoogle Scholar
  154. 154.
    King DE, Mainous AG III, Geesey ME (2008) Variation in L-arginine intake according to demographic characteristics and cardiovascular risk. Nutr Res 28:21CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Tsutsui M et al (2015) Significance of nitric oxide synthases: lessons from triple nitric oxide synthases null mice. J Pharmacol Sci 127:42–52CrossRefPubMedGoogle Scholar
  156. 156.
    Sansbury BE, Hill BG (2014) Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 73C:383–399CrossRefGoogle Scholar
  157. 157.
    Rafikov R et al (2011) eNOS activation and NO function: structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity. J Endocrinol 210:271–284CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Abudukadier A et al (2013) Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase–dependent manner in diabetic mice. Diabetes 62:3033–3043CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Shimazu T et al (2011) Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction. Am J Physiol Circ Physiol 301:H2061–H2072CrossRefGoogle Scholar
  160. 160.
    Varadharaj S et al (2017) Role of dietary antioxidants in the preservation of vascular function and the modulation of health and disease. Front Cardiovasc Med 4:64CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Yang Y, Loscalzo J (2005) S-nitrosoprotein formation and localization in endothelial cells. Proc Natl Acad Sci 102:117–122CrossRefPubMedGoogle Scholar
  162. 162.
    Daaka Y (2012) S-nitrosylation-regulated GPCR signaling. Biochim Biophys Acta 1820:743–751CrossRefPubMedGoogle Scholar
  163. 163.
    Al-Ani B et al (2006) The release of nitric oxide from S-nitrosothiols promotes angiogenesis. PLoS One 1:e25CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Kleinbongard P et al (2003) Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 35:790–796CrossRefPubMedGoogle Scholar
  165. 165.
    Moncada S, Rees DD, Schulz R, Palmer RM (1991) Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A 88:2166–2170CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Park J-H et al (2002) Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization. J Biol Chem 277:47073–47079CrossRefPubMedGoogle Scholar
  167. 167.
    Carvalho-Filho MA et al (2005) S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt. Diabetes 54:959–967CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Hobby Aggarwal
    • 1
  • Babu Nageswararao Kanuri
    • 1
    • 2
  • Madhu Dikshit
    • 3
  1. 1.Pharmacology DivisionCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Division of Endocrinology, Diabetes and MetabolismUniversity of CincinnatiCincinnatiUSA
  3. 3.Department of BiotechnologyTranslational Health Science and Technology (THSTI)FaridabadIndia

Personalised recommendations