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NO Signaling in the Cardiovascular System and Exercise

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Exercise for Cardiovascular Disease Prevention and Treatment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1000))

Abstract

Nitric oxide (NO) is a small molecule implicated in multiple signal transduction pathways thus contributing to the regulation of many cellular functions. The identification of NO synthase (NOS) isoforms and the subsequent characterization of the mechanisms of cell activation of the enzymes permitted the partial understanding of both the physiological and pathological processes. NO bioavailability plays an important role in the pathophysiology of cardiovascular disease and its reduction in endothelial cells is strictly associated to endothelial dysfunction which, in turn, correlates with cardiovascular mortality. Indeed, endothelial NO synthase (eNOS) has a key role in limiting cardiac dysfunction and remodeling in heart diseases, in part by decreasing myocyte hypertrophy. Conversely, exercise training is recommended to prevent and treat cardiovascular diseases-associated disorders at least by enhanced NO synthase activity and expression, and increased production of antioxidants, which prevents premature breakdown of NO. Exercise training may cause an improvement in endothelial function for both experimental animals and humans; Studies in both healthy subjects and patients with impaired NO-related vasorelaxation remarked exercise training ability to improve vascular structure and function and endothelial homeostasis. This chapter will briefly consider the importance of NO signaling in the maintenance of cardiovascular physiology, and discuss recent insights into the effect of exercise training on the signaling pathways that modulate NO synthesis and degradation in health and cardiovascular disease. In addition, we will highlight the molecular mechanisms via which microRNAs (miRs) target NO signaling in the cardiovascular system, and NO as a candidate molecule for development of new therapies.

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References

  1. Lundberg JO, Gladwin MT, Weitzberg E (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14(9):623–641

    Article  CAS  PubMed  Google Scholar 

  2. Ghimire K, Altmann HM, Straub A et al (2016) Nitric oxide: what’s new to NO? Am J Phys Cell Phys. doi:10.1152/ajpcell.00315.02016

  3. Saraiva RM, Hare JM (2006) Nitric oxide signaling in the cardiovascular system: implications for heart failure. Curr Opin Cardiol 21(3):221–228

    Article  PubMed  Google Scholar 

  4. Liu VW, Huang PL (2008) Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 77(1):19–29

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288(5789):373–376

    Article  CAS  PubMed  Google Scholar 

  6. Ignarro LJ, Buga GM, Wood KS et al (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84(24):9265–9269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Culotta E, Koshland DE (1992) No news is good news. Science 258(5090):1862–1865

    Article  CAS  PubMed  Google Scholar 

  8. Godo S, Shimokawa H (2016) Divergent roles of endothelial nitric oxide synthases system in maintaining cardiovascular homeostasis. Free Radic Biol Med 109:4−10 

    Google Scholar 

  9. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(7):829–837. 837a-837d

    Article  PubMed  CAS  Google Scholar 

  10. Nath AK, Madri JA (2006) The roles of nitric oxide in murine cardiovascular development. Dev Biol 292(1):25–33

    Article  CAS  PubMed  Google Scholar 

  11. Maiorana A, O’Driscoll G, Taylor R et al (2003) Exercise and the nitric oxide vasodilator system. Sports Med 33(14):1013–1035

    Article  PubMed  Google Scholar 

  12. Fernandes T, Magalhaes FC, Roque FR et al (2012) Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, −21, and −126. Hypertension 59(2):513–520

    Article  CAS  PubMed  Google Scholar 

  13. Fernandes T, Nakamuta JS, Magalhaes FC et al (2012) Exercise training restores the endothelial progenitor cells number and function in hypertension: implications for angiogenesis. J Hypertens 30(11):2133–2143

    Article  CAS  PubMed  Google Scholar 

  14. Roque FR, Briones AM, Garcia-Redondo AB et al (2013) Aerobic exercise reduces oxidative stress and improves vascular changes of small mesenteric and coronary arteries in hypertension. Br J Pharmacol 168(3):686–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ren J, Yang L, Tian W et al (2015) Nitric oxide synthase inhibition abolishes exercise-mediated protection against isoproterenol-induced cardiac hypertrophy in female mice. Cardiology 130(3):175–184

    Article  CAS  PubMed  Google Scholar 

  16. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43(2):109

    CAS  PubMed  Google Scholar 

  17. Ghafourifar P, Schenk U, Klein SD et al (1999) Mitochondrial nitric-oxide synthase stimulation causes cytochrome c release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation. J Biol Chem 274(44):31185–31188

    Article  CAS  PubMed  Google Scholar 

  18. Moncada S, Higgs EA (1995) Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J 9(13):1319–1330

    CAS  PubMed  Google Scholar 

  19. Abusoud HM, Stuehr DJ (1993) Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc Natl Acad Sci 90(22):10769

    Article  CAS  Google Scholar 

  20. Klatt P, Pfeiffer S, List BM et al (1996) Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin. J Biol Chem 271(13):7336–7342

    Article  CAS  PubMed  Google Scholar 

  21. Chen W, Xiao H, Rizzo AN et al (2013) Endothelial nitric oxide synthase dimerization is regulated by heat shock protein 90 rather than by phosphorylation. PLoS One 9(8):e105479

    Article  CAS  Google Scholar 

  22. List BM, Kloesch B, Voelker C et al (1997) Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. Biochem J 323(1):159–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6(8):662–680

    Article  CAS  PubMed  Google Scholar 

  24. Tang Y, Jiang H, Bryan NS (2011) Nitrite and nitrate: cardiovascular risk-benefit and metabolic effect. Curr Opin Lipidol 22(1):11–15

    Article  CAS  PubMed  Google Scholar 

  25. Kapil V, Milsom AB, Okorie M et al (2010) Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 56(2):274

    Article  CAS  PubMed  Google Scholar 

  26. Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78(6):931–936

    Article  CAS  PubMed  Google Scholar 

  27. Rychter M, Gaucher C, Boudier A et al (2016) S-nitrosothiols-no donors regulating cardiovascular cell proliferation: insight into intracellular pathway alterations. Int J Biochem Cell Biol 78:156

    Article  CAS  PubMed  Google Scholar 

  28. Batista WL, Ogata FT, Curcio MF et al (2013) S-nitrosoglutathione and endothelial nitric oxide synthase-derived nitric oxide regulate compartmentalized ras S-nitrosylation and stimulate cell proliferation. Antioxid Redox Signal 18(3):221–238

    Article  CAS  PubMed  Google Scholar 

  29. Thomas DD, Ridnour LA, Isenberg JS et al (2008) The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 45(1):18–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Villa LM, Salas E, Darley-Usmar VM et al (1994) Peroxynitrite induces both vasodilation and impaired vascular relaxation in the isolated perfused rat heart. Proc Natl Acad Sci U S A 91(26):12383–12387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang PL, Huang Z, Mashimo H et al (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377(6546):239–242

    Article  CAS  PubMed  Google Scholar 

  32. Lee PC, Salyapongse AN, Bragdon GA et al (1999) Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Phys 277(4 Pt 2):H1600–H1608

    CAS  Google Scholar 

  33. MacMicking JD, Nathan C, Hom G et al (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81(4):641–650

    Article  CAS  PubMed  Google Scholar 

  34. Huang PL, Dawson TM, Bredt DS et al (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75(7):1273–1286

    Article  CAS  PubMed  Google Scholar 

  35. Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284(1):1–12

    Article  Google Scholar 

  36. Wu PR, Chen BR, Hsieh CC et al (2014) The N-terminal portion of autoinhibitory element modulates human endothelial nitric-oxide synthase activity through coordinated controls of phosphorylation at Thr495 and Ser1177. Biosci Rep 34(4):443–455

    Article  CAS  Google Scholar 

  37. Schmidt A (2012) Nitric oxide signalling in vascular control and cardiovascular risk. Cardiovascular Risk Factors, Prof. Armen Gasparyan (Ed.), InTech, DOI: 10.5772/34801. Available from: https://www.intechopen.com/books/cardiovascular-risk-factors/nitric-oxide-signalling-in-vascular-control-and-cardiovascular-risk

    Google Scholar 

  38. Fulton D, Ling R, Sood SG et al (2008) Agonist-stimulated endothelial nitric oxide synthase activation and vascular relaxation role of eNOS phosphorylation at Tyr83. Circ Res 102(4):497–504

    Article  CAS  PubMed  Google Scholar 

  39. Cebova M, Kosutova M, Pechanova O (2016) Cardiovascular effects of gasotransmitter donors. Physiol Res 65(Supplementum 3):S291–S307

    CAS  PubMed  Google Scholar 

  40. Pechánová O, Varga ZV, Cebová M et al (2015) Cardiac NO signalling in the metabolic syndrome. Br J Pharmacol 172(6):1415–1433

    Article  PubMed  CAS  Google Scholar 

  41. Simon JN, Duglan D, Casadei B et al (2014) Nitric oxide synthase regulation of cardiac excitation-contraction coupling in health and disease. J Mol Cell Cardiol 73:80–91

    Article  CAS  PubMed  Google Scholar 

  42. Strijdom H, Chamane N, Lochner A (2009) Nitric oxide in the cardiovascular system: a simple molecule with complex actions. Cardiovasc J Afr 20(5):303–310

    PubMed  PubMed Central  Google Scholar 

  43. Barouch LA, Harrison RW, Skaf MW et al (2002) Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416(6878):337–339

    Article  CAS  PubMed  Google Scholar 

  44. Feron O, Belhassen L, Kobzik L et al (1996) Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem 271(37):22810–22814

    Article  CAS  PubMed  Google Scholar 

  45. Kojda G, Kottenberg K (1999) Regulation of basal myocardial function by NO. Cardiovasc Res 41(3):514–523

    Article  CAS  PubMed  Google Scholar 

  46. Murphy E, Kohr M, Menazza S et al (2014) Signaling by S-nitrosylation in the heart. J Mol Cell Cardiol 73:18–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nagpure BV, Bian JS (2016) Interaction of hydrogen sulfide with nitric oxide in the cardiovascular system. Oxidative Med Cell Longev 2016:6904327

    Article  CAS  Google Scholar 

  48. Schulz R, Kelm M, Heusch G (2004) Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res 61(3):402–413

    Article  CAS  PubMed  Google Scholar 

  49. Massion PB, Feron O, Dessy C et al (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ Res 93(5):388–398

    Article  CAS  PubMed  Google Scholar 

  50. Kelly RA, Balligand JL, Smith TW (2007) Nitric oxide and cardiac function. Life Sci 81(10):779–793

    Article  CAS  Google Scholar 

  51. Andreadou I, Iliodromitis EK, Rassaf T et al (2015) The role of gasotransmitters NO, H 2 S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. Br J Pharmacol 172:1587

    Google Scholar 

  52. Massion PB, Balligand JL (2003) Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice. J Physiol 546(Pt 1):63–75

    Article  CAS  PubMed  Google Scholar 

  53. Zhang YH, Jin CZ, Jang JH et al (2014) Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology. J Physiol 592(15):3189–3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Khan SA, Lee K, Minhas KM et al (2004) Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc Natl Acad Sci U S A 101(45):15944–15948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang YH (2016) Neuronal nitric oxide synthase in hypertension – an update. Clin Hypertens 22:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jin CZ, Jang JH, Wang Y et al (2012) Neuronal nitric oxide synthase is up-regulated by angiotensin II and attenuates NADPH oxidase activity and facilitates relaxation in murine left ventricular myocytes. J Mol Cell Cardiol 52(6):1274

    Article  CAS  PubMed  Google Scholar 

  57. Ziolo MT, Kohr MJ, Wang H (2008) Nitric oxide signaling and the regulation of myocardial function. J Mol Cell Cardiol 45(5):625–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ferreiro CR, Chagas AC, Carvalho MH et al (2004) Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease. Braz J Med Biol Res 37(9):1313–1320

    Article  CAS  PubMed  Google Scholar 

  59. Feng Q, Lu X, Jones DL et al (2001) Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104(6):700–704

    Article  CAS  PubMed  Google Scholar 

  60. Kanno S, Lee PC, Zhang Y et al (2000) Attenuation of myocardial ischemia/reperfusion injury by superinduction of inducible nitric oxide synthase. Circulation 101(23):2742–2748

    Article  CAS  PubMed  Google Scholar 

  61. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115(10):1285–1295

    PubMed  Google Scholar 

  62. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695

    Article  CAS  PubMed  Google Scholar 

  63. Sibal L, Agarwal SC, Home PD et al (2010) The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev 6(2):82–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Moncada S, Higgs EA (2006) The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 147(Suppl 1):S193–S201

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Dobutovic B, Smiljanic K, Soski S et al (2011) Nitric oxide and its role in cardiovascular diseases. Open Nitric Oxide J 3(1):65–71

    Article  CAS  Google Scholar 

  66. Karbach S, Wenzel P, Waisman A et al (2014) eNOS uncoupling in cardiovascular diseases – the role of oxidative stress and inflammation. Curr Pharm Des 20(22):3579–3594

    Article  CAS  PubMed  Google Scholar 

  67. Chen CA, Wang TY, Varadharaj S et al (2010) S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468(7327):1115–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li L, Chen W, Rezvan A et al (2011) Tetrahydrobiopterin deficiency and nitric oxide synthase uncoupling contribute to atherosclerosis induced by disturbed flow. Arterioscler Thromb Vasc Biol 31(7):1547–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hashimoto T, Sivakumaran V, Carnicer R et al (2016) Tetrahydrobiopterin protects against hypertrophic heart disease independent of myocardial nitric oxide synthase coupling. J Am Heart Assoc 5(3):e003208

    Article  PubMed  PubMed Central  Google Scholar 

  70. Thoonen R, Sips PY, Bloch KD et al (2013) Pathophysiology of hypertension in the absence of nitric oxide/cyclic GMP signaling. Curr Hypertens Rep 15(1):47–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gonzalez J, Valls N, Brito R et al (2014) Essential hypertension and oxidative stress: new insights. World J Cardiol 6(6):353–366

    Article  PubMed  PubMed Central  Google Scholar 

  72. Duplain H, Burcelin R, Sartori C et al (2001) Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104(3):342–345

    Article  CAS  PubMed  Google Scholar 

  73. Lin KF, Chao L, Chao J (1997) Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery. Hypertension 30(3 Pt 1):307–313

    Article  CAS  PubMed  Google Scholar 

  74. Zhou MS, Schulman IH, Raij L (2004) Nitric oxide, angiotensin II, and hypertension. Semin Nephrol 24(4):366–378

    Article  CAS  PubMed  Google Scholar 

  75. Mollnau H, Wendt M, Szocs K et al (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90(4):E58–E65

    Article  PubMed  Google Scholar 

  76. Forstermann U, Li H (2011) Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol 164(2):213–223

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Tsutsui M, Nakata S, Shimokawa H et al (2008) Spontaneous myocardial infarction and nitric oxide synthase. Trends Cardiovasc Med 18(8):275–279

    Article  CAS  PubMed  Google Scholar 

  78. Sutton MG, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101(25):2981–2988

    Article  CAS  PubMed  Google Scholar 

  79. Haywood GA, Tsao PS, von der Leyen HE et al (1996) Expression of inducible nitric oxide synthase in human heart failure. Circulation 93(6):1087–1094

    Article  CAS  PubMed  Google Scholar 

  80. Gilson W, Epstein FZ, Xu Y et al (2007) Borderzone contractile dysfunction is transiently attenuated and left ventricular structural remodeling is markedly reduced following reperfused myocardial infarction in inducible nitric oxide synthase knockout mice. J Am Coll Cardiol 50(18):1799–1807

    Article  CAS  PubMed  Google Scholar 

  81. Scherrer-Crosbie M, Ullrich R, Bloch KD et al (2001) Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 104(11):1286–1291

    Article  CAS  PubMed  Google Scholar 

  82. Janssens S, Pokreisz P, Schoonjans L et al (2004) Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 94(9):1256–1262

    Article  CAS  PubMed  Google Scholar 

  83. Neves VJ, Fernandes T, Roque FR et al (2014) Exercise training in hypertension: role of microRNAs. World J Cardiol 6(8):713–727

    Article  PubMed  PubMed Central  Google Scholar 

  84. Laufs U, Werner N, Link A et al (2004) Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109(2):220–226

    Article  CAS  PubMed  Google Scholar 

  85. Adams V, Linke A, Kränkel N et al (2005) Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation 111(5):555

    Article  CAS  PubMed  Google Scholar 

  86. Negrao MV, Alves CR, Alves GB et al (2010) Exercise training improves muscle vasodilatation in individuals with T786C polymorphism of endothelial nitric oxide synthase gene. Physiol Genomics 42A(1):71–77

    Article  CAS  PubMed  Google Scholar 

  87. Fernandes T, Soci UP, Oliveira EM (2011) Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants. Braz J Med Biol Res 44(9):836–847

    Article  CAS  PubMed  Google Scholar 

  88. Neves VJD, Tanno AP, Cunha TS et al (2013) Effects of nandrolone and resistance training on the blood pressure, cardiac electrophysiology, and expression of atrial β-adrenergic receptors. Life Sci 92(20–21):1029–1035

    Article  PubMed  CAS  Google Scholar 

  89. Dantas PS, Sakata MM, Perez JD et al (2016) Unraveling the role of high-intensity resistance training on left ventricle proteome: is there a shift towards maladaptation? Life Sci 152:156–164

    Article  CAS  PubMed  Google Scholar 

  90. Deprez PH, Sempoux C, De Saeger C et al (2002) Expression of cholecystokinin in the duodenum of patients with coeliac disease: respective role of atrophy and lymphocytic infiltration. Clin Sci (Lond) 103(2):171–177

    Article  CAS  Google Scholar 

  91. Da SNJ, Fernandes T, Soci UP et al (2012) Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 44(8):1453–1462

    Article  CAS  Google Scholar 

  92. Hellsten Y, Nyberg M, Jensen LG et al (2012) Vasodilator interactions in skeletal muscle blood flow regulation. J Physiol 590(24):6297–6305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Radegran G, Saltin B (1999) Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Phys 276(6 Pt 2):H1951–H1960

    CAS  Google Scholar 

  94. Gilligan DM, Panza JA, Kilcoyne CM et al (1994) Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 90(6):2853–2858

    Article  CAS  PubMed  Google Scholar 

  95. Panza JA, Casino PR, Badar DM et al (1993) Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 87(5):1475–1481

    Article  CAS  PubMed  Google Scholar 

  96. Mortensen SP, Gonzálezalonso J, Damsgaard R et al (2007) Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg. J Physiol 581(2):853–861

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Harris MB, Mitchell BM, Sood SG et al (2008) Increased nitric oxide synthase activity and Hsp90 association in skeletal muscle following chronic exercise. Eur J Appl Physiol 104(5):795–802

    Article  CAS  PubMed  Google Scholar 

  98. Tanaka LY, Bechara LR, dos Santos AM et al (2015) Exercise improves endothelial function: a local analysis of production of nitric oxide and reactive oxygen species. Nitric Oxide 45:7–14

    Article  CAS  PubMed  Google Scholar 

  99. Schuler G, Adams V, Goto Y (2013) Role of exercise in the prevention of cardiovascular disease: results, mechanisms, and new perspectives. Eur Heart J 34(24):1790–1799

    Article  CAS  PubMed  Google Scholar 

  100. Forstermann U, Munzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113(13):1708–1714

    Article  PubMed  CAS  Google Scholar 

  101. Rafiq A, Aslam K, Malik R et al (2014) C242T polymorphism of the NADPH oxidase p22PHOX gene and its association with endothelial dysfunction in asymptomatic individuals with essential systemic hypertension. Mol Med Rep 9(5):1857–1862

    Article  CAS  PubMed  Google Scholar 

  102. Peters PG, Alessio HM, Hagerman AE et al (2006) Short-term isometric exercise reduces systolic blood pressure in hypertensive adults: possible role of reactive oxygen species. Int J Cardiol 110(2):199–205

    Article  PubMed  Google Scholar 

  103. Griendling KK, FitzGerald GA (2003) Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation 108(17):2034–2040

    Article  PubMed  Google Scholar 

  104. Chen X, An X, Chen D et al (2016) Chronic exercise training improved aortic endothelial and mitochondrial function via an AMPKalpha2-dependent manner. Front Physiol 7:631

    PubMed  PubMed Central  Google Scholar 

  105. Claudio ER, Almeida SA, Mengal V, et al (2017) Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats. Braz J M Biol Res = Revista brasileira de pesquisas medicas e biologicas 50 (1):e5495

    Google Scholar 

  106. Hirai T, Zelis R, Musch TI (1995) Effects of nitric oxide synthase inhibition on the muscle blood flow response to exercise in rats with heart failure. Cardiovasc Res 30(3):469–476

    Article  CAS  PubMed  Google Scholar 

  107. Linke A, Schoene N, Gielen S et al (2001) Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training. J Am Coll Cardiol 37(2):392–397

    Article  CAS  PubMed  Google Scholar 

  108. Varin R, Mulder P, Richard V et al (1999) Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress. Circulation 99(22):2951–2957

    Article  CAS  PubMed  Google Scholar 

  109. Hambrecht R, Fiehn E, Weigl C et al (1998) Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 98(24):2709–2715

    Article  CAS  PubMed  Google Scholar 

  110. Hirai DM, Copp SW, Holdsworth CT et al (2014) Skeletal muscle microvascular oxygenation dynamics in heart failure: exercise training and nitric oxide-mediated function. Am J Physiol Heart Circ Physiol 306(5):H690–H698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hambrecht R, Adams V, Erbs S et al (2003) Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107(25):3152

    Article  CAS  PubMed  Google Scholar 

  112. Antoniades C, Tousoulis D, Tentolouris C et al (2003) Oxidative stress, antioxidant vitamins, and atherosclerosis. From basic research to clinical practice. Herz 28(7):628–638

    Article  PubMed  Google Scholar 

  113. Farah C, Kleindienst A, Bolea G et al (2013) Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites. Basic Res Cardiol 108(6):389

    Article  CAS  PubMed  Google Scholar 

  114. Zhang KR, Liu HT, Zhang HF et al (2007) Long-term aerobic exercise protects the heart against ischemia/reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism. Apoptosis 12(9):1579–1588

    Article  CAS  PubMed  Google Scholar 

  115. Otani H (2009) The role of nitric oxide in myocardial repair and remodeling. Antioxid Redox Signal 11(8):1913–1928

    Article  CAS  PubMed  Google Scholar 

  116. Yang AL, Jen CJ, Chen HI (2003) Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study. J Appl Physiol (1985) 95(3):1194–1200

    Article  CAS  Google Scholar 

  117. Bobryshev YV, Ivanova EA, Chistiakov DA et al (2016) Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis. Biomed Res Int 2016(5):1–13

    Article  CAS  Google Scholar 

  118. Indolfi C, Torella D, Coppola C et al (2002) Physical training increases eNOS vascular expression and activity and reduces restenosis after balloon angioplasty or arterial stenting in rats. Circ Res 91(12):1190–1197

    Article  CAS  PubMed  Google Scholar 

  119. Feletou M, Kohler R, Vanhoutte PM (2012) Nitric oxide: orchestrator of endothelium-dependent responses. Ann Med 44(7):694–716

    Article  CAS  PubMed  Google Scholar 

  120. Bruning RS, Sturek M (2015) Benefits of exercise training on coronary blood flow in coronary artery disease patients. Prog Cardiovasc Dis 57(5):443–453

    Article  PubMed  Google Scholar 

  121. Richter B, Niessner A, Penka M et al (2005) Endurance training reduces circulating asymmetric dimethylarginine and myeloperoxidase levels in persons at risk of coronary events. Thromb Haemost 94(6):1306–1311

    CAS  PubMed  Google Scholar 

  122. Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355

    Article  CAS  PubMed  Google Scholar 

  123. Qin S, Zhang C (2010) MicroRNAs in vascular disease. J Cardiovasc Pharmacol 57(1):8–12

    Article  CAS  Google Scholar 

  124. Soci UP, Fernandes T, Hashimoto NY et al (2011) MicroRNAs 29 are involved in the improvement of ventricular compliance promoted by aerobic exercise training in rats. Physiol Genomics 43(11):665–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Davis BN, Hata A (2009) Regulation of MicroRNA biogenesis: a miRiad of mechanisms. Cell Commun Signal 7:18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Jamaluddin MS, Weakley SM, Zhang L et al (2011) miRNAs: roles and clinical applications in vascular disease. Expert Rev Mol Diagn 11(1):79–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Krek A, Grun D, Poy MN et al (2005) Combinatorial microRNA target predictions. Nat Genet 37(5):495–500

    Article  CAS  PubMed  Google Scholar 

  128. Neves VJ, Moura MJ, Almeida BS et al (2012) Chronic stress, but not hypercaloric diet, impairs vascular function in rats. Stress-the International Journal on the Biology of Stress 15(2):138–148

    Article  CAS  Google Scholar 

  129. Neves VJ, Moura MJCS, Tamascia ML et al (2009) Proatherosclerotic effects of chronic stress in male rats: altered phenylephrine sensitivity and nitric oxide synthase activity of aorta and circulating lipids. Stress-Int J Biol Stress 12(4):320–327

    Article  CAS  Google Scholar 

  130. Boa BC, Souza M, Leite RD et al (2014) Chronic aerobic exercise associated to dietary modification improve endothelial function and eNOS expression in high fat fed hamsters. PLoS One 9(7):e102554

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lemos JR Jr, Alves CR, de Souza SB et al (2016) Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism. Physiol Genomics 48(2):116–123

    Article  CAS  PubMed  Google Scholar 

  132. Gielen S, Schuler G, Hambrecht R (2001) Exercise training in coronary artery disease and coronary vasomotion. Circulation 103(1):E1

    Article  CAS  PubMed  Google Scholar 

  133. Bai YP, Xiao S, Tang YB et al (2017) Shear stress-mediated upregulation of GTP cyclohydrolase/tetrahydrobiopterin pathway ameliorates hypertension-related decline in reendothelialization capacity of endothelial progenitor cells. J Hypertens 35(4):784–797

    Article  CAS  PubMed  Google Scholar 

  134. Zhao T, Li J, Chen AF (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299(1):E110–E116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tabuchi T, Satoh M, Itoh T et al (2012) MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci (Lond) 123(3):161–171

    Article  CAS  Google Scholar 

  136. Rippe C, Lesniewski L, Connell M et al (2010) Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. Aging Cell 36(1):304–312

    Article  CAS  Google Scholar 

  137. Donato AJ, Magerko KA, Lawson BR et al (2011) SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J Physiol 589(Pt 18):4545–4554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mattagajasingh I, Kim CS, Naqvi A et al (2007) SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 104(37):14855–14860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cacicedo JM, Gauthier MS, Lebrasseur NK et al (2011) Acute exercise activates AMPK and eNOS in the mouse aorta. Am J Physiol Heart Circ Physiol 301(4):H1255–H1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Koltai E, Szabo Z, Atalay M et al (2010) Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech Ageing Dev 131(1):21–28

    Article  CAS  PubMed  Google Scholar 

  141. de Gonzalo-Calvo D, Davalos A, Montero A et al (2015) Circulating inflammatory miRNA signature in response to different doses of aerobic exercise. J Appl Physiol (1985) 119(2):124–134

    Article  CAS  Google Scholar 

  142. Bernardo BC, Gao XM, Tham YK et al (2014) Silencing of miR-34a attenuates cardiac dysfunction in a setting of moderate, but not severe, hypertrophic cardiomyopathy. PLoS One 9(2):e90337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Marques FZ, Charchar FJ (2015) microRNAs in essential hypertension and blood pressure regulation. Adv Exp Med Biol 888:215–235

    Article  PubMed  CAS  Google Scholar 

  144. Ramasamy S, Velmurugan G, Shanmugha Rajan K et al (2015) MiRNAs with apoptosis regulating potential are differentially expressed in chronic exercise-induced physiologically hypertrophied hearts. PLoS One 10(3):e0121401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Church JE, Qian J, Kumar S et al (2010) Inhibition of endothelial nitric oxide synthase by the lipid phosphatase PTEN. Vasc Pharmacol 52(5–6):191–198

    Article  CAS  Google Scholar 

  146. Wardle SL, Bailey ME, Kilikevicius A et al (2015) Plasma microRNA levels differ between endurance and strength athletes. PLoS One 10(4):e0122107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Chistiakov DA, Sobenin IA, Orekhov AN et al (2015) Human miR-221/222 in physiological and atherosclerotic vascular remodeling. Biomed Res Int 2015(14):354517

    PubMed  PubMed Central  Google Scholar 

  148. Suarez Y, Fernandez-Hernando C, Pober JS et al (2007) Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100(8):1164–1173

    Article  CAS  PubMed  Google Scholar 

  149. Suárez Y, Sessa WC (2009) microRNAs as novel regulators of angiogenesis. Circ Res 104(4):442–454

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Liu D, Krueger J, Le Noble F (2011) The role of blood flow and microRNAs in blood vessel development. Int J Dev Biol 55(4–5):419–429

    Article  CAS  PubMed  Google Scholar 

  151. Yamakuchi M (2012) MicroRNAs in vascular biology. Int J Vasc Med 2012:794898

    PubMed  PubMed Central  Google Scholar 

  152. Sabatel C, Malvaux L, Bovy N et al (2011) MicroRNA-21 exhibits antiangiogenic function by targeting rhob expression in endothelial cells. PLoS One 6(2):e16979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kumarswamy R, Volkmann I, Jazbutyte V et al (2012) Transforming growth factor-β–induced endothelial-to-mesenchymal transition is partly mediated by MicroRNA-21. Arterioscler Thromb Vasc Biol 32(2):361–369

    Article  CAS  PubMed  Google Scholar 

  154. Huang ZP, Chen J, Seok HY et al (2013) MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress. Circ Res 112(9):1234–1243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Chen Z, Qi Y, Chao G (2015) Cardiac myocyte-protective effect of microRNA-22 during ischemia and reperfusion through disrupting the caveolin-3/eNOS signaling. Int J Clin Exp Pathol 8(5):4614–4626

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fang YC, Yeh CH (2015) Role of microRNAs in vascular remodeling. Curr Mol Med 15(8):684–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Raitoharju E, Lyytikainen LP, Levula M et al (2011) miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the tampere vascular study. Atherosclerosis 219(1):211–217

    Article  CAS  PubMed  Google Scholar 

  158. Shi L, Fleming I (2012) One miR level of control: microRNA-155 directly regulates endothelial nitric oxide synthase mRNA and protein levels. Hypertension 60(6):1381–1382

    Article  CAS  PubMed  Google Scholar 

  159. Wu XD, Zeng K, Liu WL et al (2014) Effect of aerobic exercise on miRNA-TLR4 signaling in atherosclerosis. Int J Sports Med 35(4):344–350

    PubMed  Google Scholar 

  160. Fernandes T, Barauna VG, Negrao CE et al (2015) Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am J Physiol Heart Circ Physiol 309(4):H543–H552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. De Rosa S, Curcio A, Indolfi C (2014) Emerging role of microRNAs in cardiovascular diseases. Circ J 78(3):567–575

    Article  PubMed  CAS  Google Scholar 

  162. Li P, Yin YL, Guo T et al (2011) Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo. Circulation 134(22):1752–1765

    Article  CAS  Google Scholar 

  163. Trajkovski M, Hausser J, Soutschek J et al (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474(7353):649–653

    Article  CAS  PubMed  Google Scholar 

  164. Ritchie RH, Drummond GR, Sobey CG, et al (2016) The opposing roles of NO and oxidative stress in cardiovascular disease. Pharmacol Res 116:57–69

    Google Scholar 

  165. Creager MA, Gallagher SJ, Girerd XJ et al (1992) L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 90(4):1248–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Drexler H, Zeiher AM, Meinzer K et al (1991) Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 338(8782–8783):1546–1550

    Article  CAS  PubMed  Google Scholar 

  167. Arese M, Strasly M, Ruva C et al (1995) Regulation of nitric oxide synthesis in uraemia. Nephrol Dial Transplant 10(8):1386–1397

    CAS  PubMed  Google Scholar 

  168. Bode-Boger SM, Boger RH, Alfke H et al (1996) L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study. Circulation 93(1):85–90

    Article  CAS  PubMed  Google Scholar 

  169. Judkins CP, Diep H, Broughton BRS et al (2010) Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/− mice. Am J Physiol Heart Circ Physiol 298(2):24–32

    Article  CAS  Google Scholar 

  170. Munzel T, Daiber A, Gori T (2013) More answers to the still unresolved question of nitrate tolerance. Eur Heart J 34(34):2666–2673

    Article  PubMed  CAS  Google Scholar 

  171. Nakazono K, Watanabe N, Matsuno K et al (1991) Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci 88(22):10045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Thomas SR, Witting PK, Drummond GR (2008) Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 10(10):1713–1765

    Article  CAS  PubMed  Google Scholar 

  173. Dao VT, Casas AI, Maghzal GJ et al (2015) Pharmacology and clinical drug candidates in redox medicine. Antioxid Redox Signal 23(14):1113–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Daiber A, Steven S, Weber A, et al (2016) Targeting vascular (endothelial) dysfunction. Br J Pharmacol 174(12):1591–1619

    Google Scholar 

  175. Bjelakovic G, Nikolova D, Gluud LL et al (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297(8):842–857

    Article  CAS  PubMed  Google Scholar 

  176. Bjelakovic G, Nikolova D, Gluud C (2013) Antioxidant supplements to prevent mortality. JAMA 310(11):1178–1179

    Article  CAS  PubMed  Google Scholar 

  177. Cunnington C, Van Assche T, Shirodaria C et al (2012) Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation 125(11):1356–1366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lopez A, Lorente JA, Steingrub J et al (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32(1):21–30

    Article  CAS  PubMed  Google Scholar 

  179. Lefer DJ, Nakanishi K, Johnston WE et al (1993) Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs. Circulation 88(5 Pt 1):2337–2350

    Article  CAS  PubMed  Google Scholar 

  180. Jugdutt BI, Warnica JW (1988) Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location. Circulation 78(4):906–919

    Article  CAS  PubMed  Google Scholar 

  181. Kinsella JP, Abman SH (1999) Recent developments in inhaled nitric oxide therapy of the newborn. Curr Opin Pediatr 11(2):121–125

    Article  CAS  PubMed  Google Scholar 

  182. Steinhorn RH (2011) Therapeutic approaches using nitric oxide in infants and children. Free Radic Biol Med 51(5):1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Abman SH (2013) Inhaled nitric oxide for the treatment of pulmonary arterial hypertension. Handb Exp Pharmacol 218:257–276

    Article  CAS  PubMed  Google Scholar 

  184. Ochikubo CG, Waffarn F, Turbow R et al (1997) Echocardiographic evidence of improved hemodynamics during inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatr Cardiol 18(4):282–287

    Article  CAS  PubMed  Google Scholar 

  185. Robinson JN, Banerjee R, Landzberg MJ et al (1999) Inhaled nitric oxide therapy in pregnancy complicated by pulmonary hypertension. Am J Obstet Gynecol 180(4):1045–1046

    Article  CAS  PubMed  Google Scholar 

  186. Dobyns EL, Cornfield DN, Anas NG et al (1999) Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure. J Pediatr 134(4):406–412

    Article  CAS  PubMed  Google Scholar 

  187. Clark RH, Kueser TJ, Walker MW et al (2000) Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical inhaled nitric oxide research group. N Engl J Med 342(7):469–474

    Article  CAS  PubMed  Google Scholar 

  188. Lindberg L, Rydgren G (1999) Production of nitrogen dioxide during nitric oxide therapy using the Servo Ventilator 300 during volume-controlled ventilation. Acta Anaesthesiol Scand 43(3):289

    Article  CAS  PubMed  Google Scholar 

  189. Gratziou C, Rovina N, Lignos M et al (2001) Exhaled nitric oxide in seasonal allergic rhinitis: influence of pollen season and therapy. Clin Exp Allergy 31(3):409–416

    Article  CAS  PubMed  Google Scholar 

  190. Bhushan S, Kondo K, Polhemus DJ et al (2014) Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling. Circ Res 114(8):1281–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Grasemann C, Ratjen F, Schnabel D et al (2008) Effect of growth hormone therapy on nitric oxide formation in cystic fibrosis patients. Eur Respir J 31(4):815–821

    Article  CAS  PubMed  Google Scholar 

  192. Morris CR, Kuypers FA, Larkin S et al (2000) Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease. Br J Haematol 111(2):498–500

    Article  CAS  PubMed  Google Scholar 

  193. Ghasemi A, Mehrazin F, Zahediasl S (2013) Effect of nitrate and L-arginine therapy on nitric oxide levels in serum, heart, and aorta of fetal hypothyroid rats. J Physiol Biochem 69(4):751–759

    Article  CAS  PubMed  Google Scholar 

  194. Borlaug BA, Koepp KE, Melenovsky V (2015) Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol 66(15):1672–1682

    Article  CAS  PubMed  Google Scholar 

  195. Li L, Rezvan A, Salerno JC et al (2010) GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide. Circulation research 106(2):328–336

    Google Scholar 

  196. Boon RA, Hergenreider E, Dimmeler S (2012) Atheroprotective mechanisms of shear stress-regulated microRNAs. Thrombosis and Haemostasis 108(4):616–620

    Google Scholar 

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Authors and Affiliations

  1. School of Physical Education and Sport, Laboratory of Biochemistry and Molecular Biology of the Exercise, University of Sao Paulo, Sao Paulo, Brazil

    Tiago Fernandes, Camila V. Gomes-Gatto, Noemy P. Pereira, Yahya R. Alayafi, Vander J. das Neves & Edilamar M. Oliveira

  2. Department of Exercise Physiology, King Saud University, Riyadh, Saudi Arabia

    Yahya R. Alayafi

  3. Institute of Higher Education Presidente Tancredo de Almeida Neves, Minas Gerais, Brazil

    Vander J. das Neves

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  1. Tiago Fernandes
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  2. Camila V. Gomes-Gatto
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  3. Noemy P. Pereira
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  4. Yahya R. Alayafi
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  5. Vander J. das Neves
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  6. Edilamar M. Oliveira
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Correspondence to Edilamar M. Oliveira .

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  1. Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China

    Junjie Xiao

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Fernandes, T., Gomes-Gatto, C.V., Pereira, N.P., Alayafi, Y.R., das Neves, V.J., Oliveira, E.M. (2017). NO Signaling in the Cardiovascular System and Exercise. In: Xiao, J. (eds) Exercise for Cardiovascular Disease Prevention and Treatment. Advances in Experimental Medicine and Biology, vol 1000. Springer, Singapore. https://doi.org/10.1007/978-981-10-4304-8_13

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