Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Preconditioning cardioprotection and exercise performance: a radical point of view

Abstract

It is well known that regular exercise training can reduce the incidence of coronary events and increase survival chances after myocardial infarction. Myocardial beneficial effects are due to the reduction of several cardiovascular disease risk factors, such as high cholesterol, hypertension, metabolic syndrome, obesity, etc. Moreover, exercise can reproduce the so-called “preconditioning”: the capacity of brief periods of ischemia to induce myocardial protection against ischemia/reperfusion injury. Pre- and postconditioning of the myocardium are two treatment strategies that considerably reduce post-ischemic contractile dysfunction and the amount of necrosis. Paradoxically, reactive oxygen and nitrogen species (ROS and RNS) have been identified as essential cardioprotective signaling molecules, in either pre- or postconditioning phenomena. Several clues demonstrate that preconditioning may be directly induced by exercise, thus leading to a protective phenotype at cardiac level without the necessity of causing ischemia. Also exercise appears to act as a physiological redox-sensitive stress that induces antioxidant beneficial myocardial adaptive responses at cellular level. The purpose of the present work is to review the role played by factors released during exercise in improving exercise performance and in triggering cardioprotection via a redox-sensitive mechanism.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Murray CJ, Lopez AD (1997) Alternative protections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet 349:1498–1504

  2. 2.

    Roberts CK, Barnard RJ (2005) Effects of exercise and diet on chronic disease. J Appl Physiol 98:3–30

  3. 3.

    Yusuf S, Hawken S, Ounpuu S et al (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the Interheart Study): case-control study. Lancet 364:937–952

  4. 4.

    Light S (1958) History of therapeutic exercise. In: Light S (ed) Therapeutic exercise. Elizabeth Licht, New Haven, pp 380–422

  5. 5.

    Anders J (1904) The Schott method of treating diseases of the heart and blood vessels. In: Snow W (ed) Journal of advanced therapeutics. Chatterton, Boston, pp 455–460

  6. 6.

    Morris JN, Heady JA, Raffle P et al (1953) Coronary heart disease and physical activity of work. Lancet 265:1053–1057

  7. 7.

    Kumar A, Kar S, Fay WP (2011) Thrombosis, physical activity, and acute coronary syndromes. J Appl Physiol 111:599–605

  8. 8.

    Shephard RJ, Balady GJ (1999) Exercise as cardiovascular therapy. Circulation 99:963–972

  9. 9.

    Leon AS (2000) Exercise following myocardial infarction. Sports Med 29:301–311

  10. 10.

    Hambrecht R, Walther C, Möbius-Winkler S et al (2004) Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease. Circulation 109:1371–1378

  11. 11.

    Pedersen BK, Saltin B (2006) Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports 16:3–63

  12. 12.

    Noakes TD, Higginson L, Opie LH (1983) Physical training increases ventricular fibrillation thresholds of isolated rat hearts during normoxia, hypoxia and regional ischemia. Circulation 67:24–30

  13. 13.

    Hamilton KL, Quindry JC, French JP et al (2004) MnSOD antisense treatment and exercise-induced protection against arrhythmias. Free Radic Biol Med 37:1360–1368

  14. 14.

    Quindry JC, Schreiber L, Hosick P et al (2010) Mitochondrial KATP channel inhibition blunts arrhythmia protection in ischemic exercised hearts. Am J Physiol Heart Circ Physiol 299:H175–H183

  15. 15.

    Laughlin MH, McAllister RM (1992) Exercise training-induced coronary vascular adaptation. J Appl Physiol 73:2209–2225

  16. 16.

    Laughlin MH, Pollock JS, Amann JF et al (2001) Training induces nonuniform increases in eNOS content along the coronary arterial tree. J Appl Physiol 90:501–510

  17. 17.

    Brown DA, Jew KN, Sparagna GC et al (2003) Exercise training preserves coronary flow and reduces infarct size following ischemia-reperfusion in rat heart. J Appl Physiol 95:2510–2518

  18. 18.

    Bowles DK, Farrar RP, Starnes JW (1992) Exercise training improves cardiac function after ischemia in the isolated, working rat heart. Am J Physiol Heart Circ Physiol 263:H804–H809

  19. 19.

    Locke M, Tanguay RM, Klabunde RE et al (1995) Enhanced postischemic myocardial recovery following exercise induction of HSP 72. Am J Physiol Heart Circ Physiol 269:H320–H325

  20. 20.

    Froelicher V, Battler A, McKirnam MD (1980) Physical activity and coronary heart disease. Cardiology 65:153–190

  21. 21.

    Morris JN, Everitt MG, Pollard R et al (1980) Vigorous exercise in leisure-time: protection against coronary heart disease. Lancet 2:1207–1210

  22. 22.

    Eichner ER (1983) Exercise and heart disease. Am J Med 75:1008–1023

  23. 23.

    Paffenbarger RS, Hyde RT, Wing A et al (1986) Physical activity, all-cause mortality, and longevity of college alumni. N Eng J Med 314:605–613

  24. 24.

    Powell KE, Thompson PD, Caspersen CJ et al (1987) Physical activity and the incidence of coronary heart disease. Ann Rev Public Health 8:253–287

  25. 25.

    Oldridge NB, Guyatt GH, Fischer ME et al (1988) Cardiac rehabilitation after myocardial infarction: combined experience of randomized clinical trials. JAMA 260:945–950

  26. 26.

    O’Connor GT, Buring JE, Yusaf S et al (1989) An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 80:234–244

  27. 27.

    Sandvick L, Erikssen J, Thoulaw WE et al (1993) Physical fitness as a predictor of mortality among healthy and middle aged Norwegian men. N Engl J Med 328:5343–5347

  28. 28.

    Blair SN (1994) Physical activity, fitness, and coronary heart disease. In: Bouchard C, Shephard RJ, Stephens T (eds) Physical activity, fitness and health. Human Kinetics, Champaign, pp 579–590

  29. 29.

    Hull SS Jr, Vanoli E, Adamson PB et al (1994) Exercise training confers anticipatory protection from sudden death during myocardial ischemia. Circulation 89:548–552

  30. 30.

    Myers J (2003) Exercise and cardiovascular health. Circulation 107:e2–e5

  31. 31.

    Myers J, Prakash M, Froelicher V et al (2002) Exercise capacity and mortality among men referred for exercise testing. New Engl J Med 346:793–801

  32. 32.

    Gomez-Alamillo C, Juncos LA, Cases A et al (2003) Interactions between vasoconstrictors and vasodilators in regulating hemodynamics of distinct vascular beds. Hypertension 42:831–836

  33. 33.

    Woodman CR, Muller JM, Laughlin MH et al (1997) Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol 273:H2575–H2579

  34. 34.

    Gattullo D, Pagliaro P, Marsh N et al (1999) New insight into nitric oxide and coronary circulation. Life Sci 65:2167–2174

  35. 35.

    Green DJ, Maiorana A, O’Driscoll G et al (2004) Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol 561:1–25

  36. 36.

    Hägg U, Wandt B, Bergström G et al (2005) Physical exercise capacity is associated with coronary and peripheral vascular function in healthy young adults. Am J Physiol Heart Circ Physiol 289:H1627–H1634

  37. 37.

    McCartney N (1998) Role of resistance training in heart disease. Med Sci Sports Exerc 30:S396–S402

  38. 38.

    Billman GE (2009) Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training. Am J Physiol Heart Circ Physiol 297:H1171–H1193

  39. 39.

    Giusti B, Marini M, Rossi L et al (2009) Gene expression profile of rat left ventricles reveals persisting changes following chronic mild exercise protocol: implications for cardioprotection. BMC Genomic 10:342

  40. 40.

    Marini M, Lapalombella R, Margonato V et al (2007) Mild exercise training, cardioprotection and stress genes profile. Eur J Appl Physiol 99:503–510

  41. 41.

    Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

  42. 42.

    Pagliaro P, Gattullo D, Rastaldo R et al (2001) Ischemic preconditioning: from the first to the second window of protection. Life Sci 69:1–15

  43. 43.

    Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

  44. 44.

    Brown DA, Moore RL (2007) Perspectives in innate and acquired cardioprotection: cardioprotection acquired through exercise. J Appl Physiol 103:1894–1899

  45. 45.

    Ferdinandy P, Schulz R, Baxter GF (2007) Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 59:418–458

  46. 46.

    Starnes JW, Taylor RP (2007) Exercise-induced cardioprotection: endogenous mechanisms. Med Sci Sports Exerc 39:1537–1543

  47. 47.

    Powers SK, Quindry JC, Kavazis AN (2008) Exercise-induced cardioprotection against myocardial ischemia-reperfusion injury. Free Radic Biol Med 44:193–201

  48. 48.

    Marongiu E, Crisafulli A (2014) Cardioprotection acquired through exercise: the role of ischemic preconditioning. Curr Cardiol Rev 10:336–348

  49. 49.

    Varga ZV, Giricz Z, Bencsik P et al (2015) Functional genomics of cardioprotection by ischemic conditioning and the influence of comorbid conditions: implications in target identification. Curr Drug Target. doi:10.2174/1389450116666150427154203

  50. 50.

    Penna C, Mancardi D, Rastaldo R et al (2009) Cardioprotection: a radical view Free radicals in pre and postconditioning. Biochim Biophys Acta 1787:781–793

  51. 51.

    Pagliaro P, Gattullo D, Penna C (2013) Nitroglycerine and sodium trioxodinitrate: from the discovery to the preconditioning effect. J Cardiovasc Med (Hagerstown) 14:698–704

  52. 52.

    Penna C, Angotti C, Pagliaro P (2014) Protein S-nitrosylation in preconditioning and postconditioning. Exp Biol Med (Maywood) 239:647–662

  53. 53.

    Richardson RS, Duteil S, Wary C et al (2006) Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J Physiol 571:415–424

  54. 54.

    Sõti C, Nagy E, Giricz Z et al (2005) Heat shock proteins as emerging therapeutic targets. Br J Pharmacol 146:769–780

  55. 55.

    Milano G, Corno AF, Lippa S et al (2002) Chronic and intermittent hypoxia induce different degrees of myocardial tolerance to hypoxia-induced dysfunction. Exp Biol Med (Maywood) 227:389–397

  56. 56.

    Pagliaro P, Penna C (2015) Redox signalling and cardioprotection: translatability and mechanism. Br J Pharmacol 172:1974–1995

  57. 57.

    Hausenloy DJ, Yellon DM (2007) Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev 12:217–234

  58. 58.

    Hausenloy DJ, Wynne AM, Yellon DM (2007) Ischemic preconditioning targets the reperfusion phase. Basic Res Cardiol 102:445–452

  59. 59.

    Cohen MV, Downey JM (2011) Ischemic postconditioning: from receptor to end effector. Antioxid Redox Signal 14:821–831

  60. 60.

    Hausenloy DJ, Lecour S, Yellon DM (2011) Reperfusion injury salvage kinase and survivor activating factor enhancement prosurvival signaling pathways in ischemic postconditioning: two sides of the same coin. Antioxid Redox Signal 14:893–907

  61. 61.

    Tullio F, Angotti C, Perrelli MG et al (2013) Redox balance and cardioprotection. Basic Res Cardiol 108:392

  62. 62.

    Zhao ZQ, Corvera JS, Halkos ME et al (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588

  63. 63.

    Tsang A, Hausenloy DJ, Mocanu MM et al (2004) Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95:230–232

  64. 64.

    Penna C, Cappello S, Mancardi D et al (2006) Post-conditioning reduces infarct size in the isolated rat heart: role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic Res Cardiol 101:168–179

  65. 65.

    Penna C, Mancardi D, Raimondo S et al (2008) The paradigm of postconditioning to protect the heart. J Cell Mol Med 12:435–458

  66. 66.

    Pagliaro P, Moro F, Tullio F et al (2011) Cardioprotective pathways during reperfusion: focus on redox signaling and other modalities of cell signaling. Antioxid Redox Signal 14:833–850

  67. 67.

    Ludman AJ, Yellon DM, Hausenloy DJ (2010) Cardiac preconditioning for ischaemia: lost in translation. Dis Model Mech 3:35–38

  68. 68.

    Xin P, Zhu W, Li J et al (2010) Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning. Am J Physiol Heart Circ Physiol 298:H1819–H1831

  69. 69.

    Hausenloy DJ, Yellon DM (2011) The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol 8:619–629

  70. 70.

    Przyklenk K, Whittaker P (2011) Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. J Cardiovasc Pharmacol Ther 16:255–259

  71. 71.

    Tamareille S, Mateus V, Ghaboura N et al (2011) RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning. Basic Res Cardiol 106:1329–1339

  72. 72.

    Bell RM, Yellon DM (2012) Conditioning the whole heart—not just the cardiomyocyte. J Mol Cell Cardiol 53:24–32

  73. 73.

    Schoemaker RG, van Heijningen CL (2000) Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol 278:H1571–H1576

  74. 74.

    Wang YP, Xu H, Mizoguchi K et al (2001) Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase. Cardiovasc Res 49:391–398

  75. 75.

    Heusch G, Schultz R (2002) Editorial: remote preconditioning. J Moll Cell Cardiol 34:1279–1281

  76. 76.

    Gross GJ (2005) Remote preconditioning and delayed cardioprotection in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 289:R1562–R1563

  77. 77.

    Kuzuya T, Hoshida S, Yamashita N et al (1993) Delayed effects of sub-lethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72:1293–1299

  78. 78.

    Marber MS, Latchman DS, Walker JM et al (1993) Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88:1264–1272

  79. 79.

    Bolli R (2000) The late phase of preconditioning. Circ Res 87:972–983

  80. 80.

    Crisafulli A, Melis F, Tocco F et al (2004) Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina. Am J Physiol Heart Circ Physiol 287:H235–H242

  81. 81.

    Kalakech H, Tamareille S, Pons S et al (2013) Role of hypoxia inducible factor-1α in remote limb ischemic preconditioning. J Mol Cell Cardiol 65:98–104

  82. 82.

    Dost T, Cohen MV, Downey JM (2008) Redox signaling triggers protection during the reperfusion rather than the ischemic phase of preconditioning. Basic Res Cardiol 103:378–384

  83. 83.

    Becker LB (2004) New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 61:461–470

  84. 84.

    Asimakis GK, Inners-McBride K, Medellin G et al (1992) Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart. Am J Physiol Heart Circ Physiol 263:H887–H894

  85. 85.

    Vanden Hoek T, Becker LB, Shao ZH, Li CQ et al (2000) Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 86:541–548

  86. 86.

    Liu Y, Yang XM, Iliodromitis EK et al (2008) Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. Basic Res Cardiol 103:54–59

  87. 87.

    Inserte J, Ruiz-Meana M, Rodríguez-Sinovas A et al (2011) Contribution of delayed intracellular pH recovery to ischemic postconditioning protection. Antioxid Redox Signal 14:923–939

  88. 88.

    Simkhovich BZ, Whittaker P, Przyklenk K et al (1995) Transient pre-ischemic acidosis protects the isolated rabbit heart subjected to 30 minutes, but not 60 minutes, of global ischemia. Basic Res Cardiol 90:397–403

  89. 89.

    Penna C, Rastaldo R, Mancardi D et al (2006) Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K + channel and protein kinase C activation. Basic Res Cardiol 101:180–189

  90. 90.

    Leeuwenburgh C, Ji LL (1995) Glutathione depletion in rested and exercised mice: biochemical consequence and adaptation. Arch Biochem Biophys 316:941–949

  91. 91.

    Liu J, Yeo HC, Overvik-Douki E et al (2000) Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. J Appl Physiol (1985) 89:21–28

  92. 92.

    Itoh M, Oh-Ishi S, Hatao H et al (2004) Effects of dietary calcium restriction and acute exercise on the antioxidant enzyme system and oxidative stress in rat diaphragm. Am J Physiol Regul Integr Comp Physiol 287:R33–R38

  93. 93.

    Boudreau J, Quadrilatero J, Hoffman-Goetz L (2005) Voluntary training in mice and submandibular lymphocyte response to acute exercise. Med Sci Sports Exerc 37:2038–2045

  94. 94.

    Mercken EM, Hageman GJ, Schols AM et al (2005) Rehabilitation decreases exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 172:994–1001

  95. 95.

    Quadrilatero J, Hoffman-Goetz L (2005) Mouse thymocyte apoptosis and cell loss in response to exercise and antioxidant administration. Brain Behav Immun 19:436–444

  96. 96.

    Sureda A, Tauler P, Aguiló A et al (2005) Relation between oxidative stress markers and antioxidant endogenous defences during exhaustive exercise. Free Radic Res 39:1317–1324

  97. 97.

    McAnulty SR, Nieman DC, Fox-Rabinovich M et al (2010) Effect of n-3 fatty acids and antioxidants on oxidative stress after exercise. Med Sci Sports Exerc 42:1704–1711

  98. 98.

    Krüger K, Frost S, Most E et al (2009) Exercise affects tissue lymphocyte apoptosis via redox-sensitive and Fas-dependent signaling pathways. Am J Physiol Regul Integr Comp Physiol 296:R1518–R1527

  99. 99.

    Prigol M, Luchese C, Nogueira CW (2009) Antioxidant effect of diphenyl diselenide on oxidative stress caused by acute physical exercise in skeletal muscle and lungs of mice. Cell Biochem Funct 27:216–222

  100. 100.

    Lappalainen Z, Lappalainen J, Laaksonen DE et al (2010) Acute exercise and thioredoxin-1 in rat brain, and alpha-lipoic acid and thioredoxin-interacting protein response, in diabetes. Int J Sport Nutr Exerc Metab 20:206–215

  101. 101.

    Nie J, Close G, George KP et al (2010) Temporal association of elevations in serum cardiac troponin T and myocardial oxidative stress after prolonged exercise in rats. Eur J Appl Physiol 110:1299–1303

  102. 102.

    Alessio HM, Hagerman AE, Fulkerson BK et al (2000) Generation of reactive oxygen species after exhaustive aerobic and isometric exercise. Med Sci Sports Exerc 32:1576–1581

  103. 103.

    Miyazaki H, Oh-ishi S, Ookawara T et al (2001) Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur J Appl Physiol 84:1–6

  104. 104.

    Watson TA, MacDonald-Wicks LK et al (2005) Oxidative stress and antioxidants in athletes undertaking regular exercise training. Int J Sport Nutr Exerc Metab 15:131–146

  105. 105.

    Bloomer RJ, Fry AC, Falvo MJ et al (2007) Protein carbonyls are acutely elevated following single set anaerobic exercise in resistance trained men. J Sci Med Sport 10:411–417

  106. 106.

    Fisher-Wellman K, Bloomer RJ (2009) Acute exercise and oxidative stress: a 30 year history. Dyn Med 8:1

  107. 107.

    Copp SW, Ferreira LF, Herspring KF et al (2009) The effects of antioxidants on microvascular oxygenation and blood flow in skeletal muscle of young rats. Exp Physiol 94:961–971

  108. 108.

    Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45:410–418

  109. 109.

    Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327–336

  110. 110.

    Kojda G, Cheng YC, Burchfield J et al (2001) Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103:2839–2844

  111. 111.

    Lauer N, Suvorava T, Rüther U et al (2005) Critical involvement of hydrogen peroxide in exercise-induced up-regulation of endothelial NO synthase. Cardiovasc Res 65:254–262

  112. 112.

    Noble EG, Shen GX (2012) Impact of exercise and metabolic disorders on heat shock proteins and vascular inflammation. Autoimmune Dis 2012:836519

  113. 113.

    Essig DA, Borger DR, Jackson DA (1997) Induction of heme oxygenase-1 (HSP32) mRNA in skeletal muscle following contractions. Am J Physiol 272:C59–C67

  114. 114.

    Esposito F, Ronchi R, Milano G et al (2011) Myocardial tolerance to ischemia-reperfusion injury, training intensity and cessation. Eur J Appl Physiol 111:859–868

  115. 115.

    Candilio L, Hausenloy DJ, Yellon DM (2011) Remote ischemic conditioning: a clinical trial’s update. J Cardiovasc Pharmacol Ther 16:304–312

  116. 116.

    Candilio L, Malik A, Hausenloy DJ (2013) Protection of organs other than the heart by remote ischemic conditioning. J Cardiovasc Med (Hagerstown) 14:193–205

  117. 117.

    Vinten-Johansen J, Shi W (2013) The science and clinical translation of remote postconditioning. J Cardiovasc Med (Hagerstown) 14:206–213

  118. 118.

    Michelsen MM, Støttrup NB, Schmidt MR et al (2012) Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. Basic Res Cardiol 107:260

  119. 119.

    Jean-St-Michel E, Manlhiot C, Li J et al (2011) Remote preconditioning improves maximal performance in highly trained athletes. Med Sci Sports Exerc 43:1280–1286

  120. 120.

    Yamashita N, Hoshida S, Otsu K et al (1999) Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med 189:1699–1706

  121. 121.

    Akita Y, Otani H, Matsuhisa S et al (2007) Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redoxsensitive activation of eNOS and upregulation of iNOS. Am J Physiol Heart Circ Physiol 292:H2051–H2059

  122. 122.

    Nelson M, Harris M, Boluyt M et al (2011) Effect of N-2-mercaptopropionyl glycine on exercise-induced cardiac adaptations. Am J Physiol Regul Integr Comp Physiol 300:R993–R1000

  123. 123.

    Sanchez G, Escobar M, Pedrozo Z et al (2008) Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection. Cardiovasc Res 77:380–386

  124. 124.

    Ji LL, Gomez-Cabrera MC, Vina J (2006) Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann NY Acad Sci 1067:425–435

  125. 125.

    Judge S, Jang YM, Smith A et al (2005) Exercise by lifelong voluntary wheel running reduces subsarcolemmal and interfibrillar mitochondrial hydrogen peroxide production in the heart. Am J Physiol Regul Integr Comp Physiol 289:R1564–R1572

  126. 126.

    Powers SK, Criswell D, Lawler J et al (1993) Rigorous exercise training increases superoxide dismutase activity in ventricular myocardium. Am J Physiol Heart Circ Physiol 265:H2094–H2098

  127. 127.

    Lennon SL, Quindry JC, French JP et al (2004) Exercise and myocardial tolerance to ischaemia-reperfusion. Acta Physiol Scand 182:161–169

  128. 128.

    Chicco AJ, Hydock DS, Schneider CM et al (2006) Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol 100:519–527

  129. 129.

    Dickson EW, Hogrefe CP, Ludwig PS et al (2008) Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism. Am J Physiol Heart Circ Physiol 294:H402–H408

  130. 130.

    Brown DA, Lynch JM, Armstrong CJ et al (2005) Susceptibility of the heart to ischaemiareperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 564:619–630

  131. 131.

    Husain K (2003) Interaction of physical training and chronic nitroglycerin treatment on blood pressure, nitric oxide, and oxidants/antioxidants in the rat heart. Pharmacol Res 48:253–261

  132. 132.

    Chaves EA, Pereira-Junior PP et al (2006) Nandrolone decanoate impairs exercise-induced cardioprotection: role of antioxidant enzymes. J Steroid Biochem Mol Biol 99:223–230

  133. 133.

    Kakarla P, Vadluri G, Reddy KS et al (2005) Vulnerability of the mid aged rat myocardium to the age-induced oxidative stress: influence of exercise training on antioxidant defense system. Free Radic Res 39:1211–1217

  134. 134.

    Lawler JM, Kwak HB, Kim JH et al (2009) Exercise training inducibility of MnSOD protein expression and activity is retained while reducing prooxidant signaling in the heart of senescent rats. Am J Physiol Regul Integr Comp Physiol 296:R1496–R1502

  135. 135.

    Demirel HA, Powers SK, Zergeroglu MA et al (2001) Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. J Appl Physiol 91:2205–2212

  136. 136.

    Taylor RP, Ciccolo JT, Starnes JW (2003) Effect of exercise training on the ability of the rat heart to tolerate hydrogen peroxide. Cardiovasc Res 58:575–581

  137. 137.

    French JP, Hamilton KL, Quindry JC et al (2008) Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. FASEB J 22:2862–2871

  138. 138.

    Ramires PR, Ji LL (2001) Glutathione supplementation and training increases myocardial resistance to ischemia-reperfusion in vivo. Am J Physiol Heart Circ Physiol 281:H679–H688

  139. 139.

    Jakeman P, Maxwell S (1993) Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise. Eur J Appl Physiol Occup Physiol 67:426–430

  140. 140.

    Shafat A, Butler P, Jensen RL et al (2004) Effects of dietary supplementation with vitamins C and E on muscle function during and after eccentric contractions in humans. Eur J Appl Physiol 93:196–202

  141. 141.

    Gomez-Cabrera MC, Domenech E, Romagnoli M et al (2008) Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 87:142–149

  142. 142.

    Ristow M, Zarse K, Oberbach A et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 106:8665–86670

  143. 143.

    Yfanti C, Akerström T, Nielsen S et al (2010) Antioxidant supplementation does not alter endurance training adaptation. Med Sci Sports Exerc 42:1388–1395

  144. 144.

    Kyparos A, Sotiriadou S, Mougios V et al (2011) Effect of 5-day vitamin E supplementation on muscle injury after downhill running in rats. Eur J Appl Physiol 111:2557–2569

  145. 145.

    Theodorou AA, Nikolaidis MG, Paschalis V et al (2011) No effect of antioxidant supplementation on muscle performance and blood redox status adaptations to eccentric training. Am J Clin Nutr 93:1373–1383

  146. 146.

    Close GL, Ashton T, Cable T et al (2006) Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process. Br J Nutr 95:976–981

  147. 147.

    Kinnunen S, Oksala N, Hyyppä S et al (2009) alpha-Lipoic acid modulates thiol antioxidant defenses and attenuates exercise-induced oxidative stress in standardbred trotters. Free Radic Res 43:697–705

  148. 148.

    McAnulty SR, McAnulty LS, Nieman DC et al (2005) Effect of alpha-tocopherol supplementation on plasma homocysteine and oxidative stress in highly trained athletes before and after exhaustive exercise. J Nutr Biochem 16:530–537

  149. 149.

    Radak Z, Chung HY, Koltai E et al (2008) Exercise, oxidative stress and hormesis. Ageing Res Rev 7:34–42

  150. 150.

    Duncker DJ, Bache RJ (2008) Regulation of coronary blood flow during exercise. Physiol Rev 88:1009–1086

  151. 151.

    Pagliaro P Exercise and vascular endothelium functions. In: New insight into cardiovascular apparatus during exercise. Physiological and physio-pathological aspects, 207 Research SignPost

  152. 152.

    Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81:1415–1459

  153. 153.

    Balligand JL, Feron O, Dessy C (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89:481–534

  154. 154.

    Baumbach GL (1991) Is pulse pressure a stimulus for altered vascular structure in chronic hypertension? Hypertension 18:728–729

  155. 155.

    Awolesi MA, Sessa WC, Sumpio BE (1995) Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest 96:1449–1454

  156. 156.

    Pagliaro P, Senzaki H, Paolocci N et al (1999) Specificity of synergistic coronary flow enhancement by adenosine and pulsatile perfusion in the dog. J Physiol 520:271–280

  157. 157.

    Gielen S, Schuler G, Adams V (2010) Cardiovascular effects of exercise training: molecular mechanisms. Circulation 122:1221–1238

  158. 158.

    Hwang MH, Kim S (2014) Type 2 diabetes: endothelial dysfunction and exercise. J Exerc Nutr Biochem 18:239–247

  159. 159.

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

  160. 160.

    Fukai T, Siegfried MR, Ushio-Fukai M et al (2000) Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest 105:1631–1639

  161. 161.

    Oltman CL, Parker JL, Adams HR et al (1992) Effects of exercise training on vasomotor reactivity of porcine coronary arteries. Am J Physiol 263:H372–H382

  162. 162.

    Prior BM, Lloyd PG, Ren J et al (2003) Arteriogenesis: role of nitric oxide. Endothelium 10:207–216

  163. 163.

    Higashi Y, Sasaki S, Kurisu S et al (1999) Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 100:1194–1202

  164. 164.

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

  165. 165.

    Penna C, Granata R, Tocchetti CG et al (2015) Endogenous cardioprotective agents: role in pre and postconditioning. Curr Drug Target. doi:10.2174/1389450116666150309115536

  166. 166.

    Ntaios G, Gatselis NK, Makaritsis K et al (2013) Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis 227:216–221

  167. 167.

    Sakurai T, Ogasawara J, Kizaki T et al (2013) The effects of exercise training on obesity-induced dysregulated expression of adipokines in white adipose tissue. Int J Endocrinol 2013:801743

  168. 168.

    Golbidi S, Laher I (2014) Exercise induced adipokine changes and the metabolic syndrome. J Diabetes Res 2014:726861

  169. 169.

    Maguire JJ, Kleinz MJ, Pitkin SL et al (2009) [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 54:598–604

  170. 170.

    Zhen EY, Higgs RE, Gutierrez JA (2013) Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal Biochem 442:1–9

  171. 171.

    Folino A, Montarolo PG, Samaja M et al (2015) Effects of apelin on the cardiovascular system. Heart Fail Rev. doi:10.1007/s10741-015-9475-x

  172. 172.

    Cox CM, D’Agostino SL, Miller MK et al (2006) Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev Biol 296:177–189

  173. 173.

    Kleinz MJ, Davenport AP (2004) Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul Pept 118:119–125

  174. 174.

    Ashley EA, Powers J, Chen M et al (2005) The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res 65:73–82

  175. 175.

    Szokodi I, Tavi P, Földes G et al (2002) Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 91:434–440

  176. 176.

    Dai T, Ramirez-Correa G, Gao WD (2006) Apelin increases contractility in failing cardiac muscle. Eur J Pharmacol 553:222–228

  177. 177.

    Farkasfalvi K, Stagg MA, Coppen SR et al (2007) Direct effects of apelin on cardiomyocytes contractility and electrophysiology. Biochem Biophys Res Commun 357:889–895

  178. 178.

    Rastaldo R, Cappello S, Folino A et al (2011) Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool? Antioxid Redox Signal 14:909–922

  179. 179.

    Tatemoto K, Takayama K, Zou MX et al (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 99:87–92

  180. 180.

    Hashimoto T, Kihara M, Ishida J et al (2006) Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 26:1267–1272

  181. 181.

    Fujie S, Sato K, Miyamoto-Mikami E et al (2014) Reduction of arterial stiffness by exercise training is associated with increasing plasma apelin level in middle-aged and older adults. PLoS ONE 9:e93545

  182. 182.

    Jia YX, Lu ZF, Zhang J et al (2007) Apelin activates l-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides 28:2023–2029

  183. 183.

    Zhong JC, Yu XY, Huang Y et al (2007) Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res 74:388–395

  184. 184.

    Zhang J, Ren CX, Qi YF et al (2006) Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats. Life Sci 79:1153–1159

  185. 185.

    Kadoglou NP, Fotiadis G, Kapelouzou A et al (2013) The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with type 2 diabetes. Diabet Med 30:e41–e50

  186. 186.

    Krist J, Wieder K, Klöting N et al (2013) Effects of weight loss and exercise on apelin serum concentrations and adipose tissue expression in human obesity. Obes Facts 6:57–69

  187. 187.

    Sheibani S, Hanachi P, Refahiat MA (2012) Effect of aerobic exercise on serum concentration of apelin, TNFα and insulin in obese women. Iran J Basic Med Sci 15:1196–1201

  188. 188.

    Besse-Patin A, Montastier E, Vinel C et al (2014) Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int J Obes (Lond) 38:707–713

  189. 189.

    Rastaldo R, Cappello S, Folino A et al (2011) Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol 300:H2308–H2315

  190. 190.

    Simpkin JC, Yellon DM, Davidson SM et al (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Res Cardiol 102:518–528

  191. 191.

    Zeng XJ, Zhang LK, Wang HX et al (2009) Apelin protects heart against ischemia/reperfusion injury in rat. Peptides 30:1144–1152

  192. 192.

    Wang C, Liu N, Luan R et al (2013) Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2 + -ATPase and ryanodine receptor. Cardiovasc Res 100:114–124

  193. 193.

    Pisarenko O, Shulzhenko V, Studneva I et al (2015) Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischemia-reperfusion injury. Br J Pharmacol 172:2933–2945

  194. 194.

    Pisarenko OI, Lankin VZ, Konovalova GG et al (2014) Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion. Mol Cell Biochem 391:241–250

  195. 195.

    Foussal C, Lairez O, Calise D et al (2010) Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett 584:2363–2370

  196. 196.

    Frier BC, Williams DB, Wright DC (2009) The effects of apelin treatment on skeletal muscle mitochondrial content. Am J Physiol Regul Integr Comp Physiol 297:R1761–R1768

  197. 197.

    Mancardi D, Penna C, Merlino A et al (2009) Physiological and pharmacological features of the novel gasotransmitter: hydrogen sulfide. Biochim Biophys Acta 1787:864–872

  198. 198.

    Lennon SL, Quindry J, Hamilton KL et al (2004) Loss of exercise-induced cardioprotection after cessation of exercise. J Appl Physiol (1985) 96:1299–1305

  199. 199.

    Cosby K, Partovi KS, Crawford JH et al (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9:1498–1505

  200. 200.

    Foresti R, Bani-Hani MG, Motterlini R (2008) Use of carbon monoxide as a therapeutic agent: promises and challenges. Intensive Care Med 34:649–658

  201. 201.

    Vandegriff KD, Young MA, Lohman J et al (2008) CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats. Br J Pharmacol 154:1649–1661

  202. 202.

    Essig DA, Borger DR, Jackson DA (1997) Induction of heme oxygenase-1 (HSP32) mRNA in skeletal muscle following contractions. Am J Physiol 272:C59–C67

  203. 203.

    Calvert JW, Condit ME, Aragón JP et al (2011) Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ Res 108:1448–1458

  204. 204.

    Tavernier G, Toumaniantz G, Erfanian M et al (2003) beta3-Adrenergic stimulation produces a decrease of cardiac contractility ex vivo in mice overexpressing the human beta3-adrenergic receptor. Cardiovasc Res 59:288–296

  205. 205.

    Banquet S, Delannoy E, Agouni A et al (2011) Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in β-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery. Cell Signal 23:1136–1143

  206. 206.

    Bhambhani Y, Singh M (1991) Physiological effects of hydrogen sulfide inhalation during exercise in healthy men. J Appl Physiol (1985) 71:1872–1877

  207. 207.

    Yong QC, Lee SW, Foo CS et al (2008) Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. Am J Physiol Heart Circ Physiol 2008(295):H1330–H1340

  208. 208.

    Kang B, Hong J, Xiao J et al (2014) Involvement of miR-1 in the protective effect of hydrogen sulfide against cardiomyocyte apoptosis induced by ischemia/reperfusion. Mol Biol Rep 41:6845–6853

  209. 209.

    Abou-Hamdan A, Guedouari-Bounihi H, Lenoir V et al (2015) Oxidation of H2S in mammalian cells and mitochondria. Methods Enzymol 554:201–228

  210. 210.

    Veeranki S, Tyagi SC (2014) Role of hydrogen sulfide in skeletal muscle biology and metabolism. Nitric Oxide 46:66–71

  211. 211.

    de Groot PCE, Thijssen DHJ, Sanchez M et al (2010) Ischemic preconditioning improves maximal performance in humans. Eur J Appl Physiol 108:141–146

  212. 212.

    Crisafulli A, Tangianu F, Tocco F et al (2011) Ischemic preconditioning of the muscle improves maximal exercise performance but not maximal oxygen uptake in humans. J Appl Physiol 111:530–536

  213. 213.

    Bailey TG, Jones H, Gregson W et al (2012) Effect of ischemic preconditioning on lactate accumulation and running performance. Med Sci Sport Exerc 44:2084–2089

  214. 214.

    Clevidence MW, Mowery RE, Kushnick MR (2012) The effects of ischemic preconditioning on aerobic and anaerobic variables associated with submaximal cycling performance. Eur L Appl Physiol 112:3649–3654

  215. 215.

    Gibson N, White J, Neish M et al (2013) Effect of ischemic preconditioning on land-based sprinting in team-sport athletes. Int J Sports Physiol Perform 8:671–676

  216. 216.

    Tocco F, Marongiu E, Ghiani G et al (2015) Muscle ischemic preconditioning does not improve performance during self-paced exercise. Int J Sports Med 36:9–15

  217. 217.

    Hittinger EA, Maher JL, Nash MS et al (2015) Ischemic preconditioning does not improve peak exercise capacity at sea level or simulated high altitude in trained male cyclists. Appl Physiol Nutr Metab 40:65–71

  218. 218.

    Paixao RC, da Mota GR, Marocolo M (2014) Acute effect of ischemic preconditioning is detrimental to anaerobic performance in cyclists. Int J Sports Med 35:912–915

  219. 219.

    Lalonde F, Curnier DY (2015) Can anaerobic performance be improved by remote ischemic preconditioning? J Strength Cond Res 29:80–85

  220. 220.

    Barbosa TC, Machado AC, Braz ID et al (2015) Remote ischemic preconditioning delays fatigue development during handgrip exercise. Scand J Med Sci Sports 25:356–364

  221. 221.

    Pang CY, Yang RZ, Zhong A et al (1995) Acute ischemic preconditioning protects against skeletal muscle infarction in the pig. Cardiovasc Res 29:782–788

  222. 222.

    Reid MB (1985) Invited review: redox modulation of skeletal muscle contraction: what we know and what we don’t. J Appl Physiol 90:724–731

Download references

Acknowledgments

The authors are grateful to MIUR for financial support.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For the quoted articles of the authors in which animal or humans were used, all applicable international, national, and/or institutional guidelines for the care and use of animals were followed and the informed consent by humans obtained.

Author information

Correspondence to Pasquale Pagliaro.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Crisafulli, A., Mancardi, D., Marongiu, E. et al. Preconditioning cardioprotection and exercise performance: a radical point of view. Sport Sci Health 11, 137–151 (2015). https://doi.org/10.1007/s11332-015-0225-1

Download citation

Keywords

  • Exercise performance
  • Preconditioning
  • Postconditioning
  • Endothelial factors
  • Redox balance