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Impact of Perinatal Chronic Hypoxia on Cardiac Tolerance to Acute Ischemia

  • Bohuslav Ostadal
  • I. Ostadalova
  • F. Kolar
  • I. Netuka
  • O. Szarszoi
Chapter

Abstract

Perinatal period is critical for the normal cardiac development, and different interventions imposed on the heart may significantly influence myocardial structure and function. Perinatal hypoxemia, although transient, may thus have serious early and late consequences on the cardiovascular system. Epidemiological and experimental studies have repeatedly suggested a possible link between perinatal hypoxia and increased sensitivity to ischemia/reperfusion (I/R) injury in adults. The mechanisms of this increased susceptibility are not known at present. It has been found that prenatal chronic hypoxia sensitizes the apoptosis pathway in the adult male heart in response to I/R stimulation. In addition, cardiac heat shock proteins (Hsp) 70 expression was significantly lower in prenatal hypoxic hearts than in controls; this fact may play a role in the increased susceptibility of the adult heart to I/R injury. The decreased eNOS levels in adult prenatal hypoxic hearts may also contribute to their increased sensitivity. These studies suggest that chronic hypoxic exposure during early development may cause in utero or neonatal programming of several genes which can play an important role in the increased susceptibility of the adult male heart to I/R injury. Furthermore, it has been observed in the rat model that late myocardial effects of chronic hypoxia, experienced in early life, may be sex-dependent. Unlike in males, perinatal exposure to chronic hypoxia significantly increased cardiac tolerance to acute I/R injury in adult females, expressed as the lower incidence of ischemic arrhythmias, decreased infarct size, decreased cardiac enzyme release, and increased postischemic recovery of left ventricular function. It was suggested that these sex-dependent changes may be due to differences in fetal programming of PKCε gene expression, which play a pivotal role in cardioprotection; down-regulation of PKCε function was observed in the hearts of adult male offspring only. These results would have important clinical implications, since cardiac sensitivity to oxygen deprivation in adult patients may be significantly influenced by perinatal hypoxia in a sex-dependent manner.

Keywords

Perinatal period Fetal heart Neonatal heart Cardiac development Mitochondrial development Chronic hypoxia Cardiac tolerance to ischemia Infarct size Arrhythmias Barker’s concept Ischemia/reperfusion injury Prenatal hypoxia Early postnatal hypoxia Late effects of perinatal hypoxia Sex-dependent changes 

Notes

Acknowledgments

This study was supported by grants MSMT 1 M0510 and AVOZ 50110509.

References

  1. 1.
    Barker DJ, Osmond C, Golding J, et al. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Xue Q, Zhang L. Prenatal hypoxia causes a sex-dependent increase in heart susceptibility to ischaemia and reperfusion injury in adult male offspring: role of protein kinase Cε. J Pharmacol Exp Therap. 2009;330:624–32.CrossRefGoogle Scholar
  3. 3.
    Giussani DA, Phillips PS, Anstee S, et al. Effects of altitude versus economic status on birth weight and body shape at birth. Pediatr Res. 2001;49:490–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Rohlicek CV, Matsuoka T, Saiki C. Cardiovascular response to acute hypoxemia in adult rats hypoxemic neonatally. Cardiovasc Res. 2002;53:263–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Nollert G, Fischlein T, Bouterwek S, et al. Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol. 1997;30:1374–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Netuka I, Szarszoi O, Maly J, et al. Effect of perinatal hypoxia on cardiac tolerance to acute ischaemia in adult male and female rats. Clin Exp Pharmacol Physiol. 2006;33:714–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Krecek J. The weanling period as a critical period of development. In: Krecek J, editor. The post-natal development of phenotype. Prague: Academia; 1970. p. 33–44.Google Scholar
  8. 8.
    Eastman NJ. Mount Everest in utero. President’s address. Am J Obstet Gynecol. 1954;67:701–11.PubMedGoogle Scholar
  9. 9.
    Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432:1032–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Mühlfeld C, Singer D, Engelhardt N, et al. Electron microscopy and microcalorimetry of the postnatal rat heart (Rattus norvegicus). Comp Biochem Physiol A Mol Integr Physiol. 2005;141:310–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Ostadalova I, Charvatova Z, Wilhelm J. Lipofuscin-like pigments in the rat heart during early postnatal development: effect of selenium supplementation. Physiol Res. 2010;59:881–6.PubMedGoogle Scholar
  12. 12.
    Ostadal B, Wachtlova M, Bily J, et al. Weight of the heart in the rats before and after birth. Physiol bohemoslov. 1967;16:111–9.Google Scholar
  13. 13.
    Ostadalova I, Kolar F, Ostadal B, et al. Early postnatal development of contractile performance and responsiveness to Ca2+, verapamil and ryanodine in the isolated rat heart. J Mol Cell Cardiol. 1993;25:733–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Li F, Wang X, Capasso JM, et al. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28:1737–46.PubMedCrossRefGoogle Scholar
  15. 15.
    Rakusan K. Vascularization of the heart during normal and pathological growth. Adv Org Biol. 1999;7:130–53.Google Scholar
  16. 16.
    Skarka L, Bardova K, Brauner P, et al. Expression of mitochondrial uncoupling protein 3 and adenine nucleotide translocase 1 genes in developing rat heart: putative involvement in control of mitochondrial membrane potential. J Mol Cell Cardiol. 2003;35:321–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Nijjar MS, Dhalla NS. Biochemical basis of calcium handling in developing myocardium. In: Ostadal B, Nagano M, Takeda N, Dhalla NS, editors. The developing heart. Philadelphia, P.A.: Lippincott; 1997. p. 189–217.Google Scholar
  18. 18.
    Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev. 1999;79:635–59.PubMedGoogle Scholar
  19. 19.
    Ostadalova I, Ostadal B, Kolar F. Effect of prenatal hypoxia on contractile performance and responsiveness to Ca2+ in the isolated perinatal rat heart. Physiol Res. 1995;44:135–7.PubMedGoogle Scholar
  20. 20.
    Babicky A, Ostadalova I, Parizek J, et al. Initial solid food intake and growth of young rats in nests of different sizes. Physiol Bohemoslov. 1973;22:557–66.PubMedGoogle Scholar
  21. 21.
    Gilbert RD. Fetal myocardial responses to long-term hypoxemia. Comp Biochem Physiol. 1998;3:669–74.Google Scholar
  22. 22.
    Ohtsuka T, Gilbert RD. Cardiac enzyme activities in fetal and adult pregnant and non pregnant sheep exposed to high altitude hypoxemia. J Appl Physiol. 1995;79:1286–9.PubMedGoogle Scholar
  23. 23.
    Murotsuki J, Challis JR, Han VK, et al. Chronic fetal placental embolization and hypoxaemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol Regul Integr Comp Physiol. 1997;272:R201–7.Google Scholar
  24. 24.
    Martin C, Yu AY, Jiang BH, et al. Cardiac hypertrophy in chronically anemic fetal sheep: increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1. Am J Obstet Gynecol. 1998;178:527–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Han HC, Austin KJ, Nathanielsz PVV, et al. Maternal nutrient restriction alters gene expression in the ovine fetal heart. J Physiol. 2004;555:111–21.CrossRefGoogle Scholar
  26. 26.
    Bae S, Xiao Y, Li G, et al. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol. 2003;285:H983–90.PubMedGoogle Scholar
  27. 27.
    Patterson AJ, Chen M, Xue Q, et al. Chronic prenatal hypoxia induces epigenetic programming of PKCε gene expression in rat hearts. Circulation Res. 2010;107:365–73.PubMedCrossRefGoogle Scholar
  28. 28.
    Verburg BO, Jaddoe VW, Wladimiroff JW, et al. Fetal hemodynamic adaptive changes related to intrauterine growth: the generation R study. Circulation. 2008;117:649–59.PubMedCrossRefGoogle Scholar
  29. 29.
    Chvojkova Z, Ostadalova I, Ostadal B. Low body weight and cardiac tolerance to ischemia in neonatal rats. Physiol Res. 2005;54:357–62.PubMedGoogle Scholar
  30. 30.
    Mortola JP, Xu L, Lauzon A-M. Body growth, lung and heart weight, and DNA content in newborn rats exposed to different levels of chronic hypoxia. Can J Physiol Pharmacol. 1990;68:1590–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Naye RL. Organ and cellular development in mice growing at simulated high altitude. Lab Invest. 1966;15:700–6.Google Scholar
  32. 32.
    Bai SL, Campbell SE, Moore JA, et al. Influence of age, growth, and sex on cardiac myocyte size and number in rats. Anat Rec. 1990;226:207–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Bell JM, Slotkin TA. Postnatal nutritional status influences development of cardiac adrenergic receptor binding sites. Brain Res Bull. 1988;21:893–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Ostadalova I, Ostadal B. Ontogenetic differences in isoproterenol induced 85 Sr uptake in the myocardium. In: Nagano M, Takeda N, Dhalla NS, editors. The cardiomyopathic heart. New York: Raven; 1994. p. 395–400.Google Scholar
  35. 35.
    Bell JM, Whitmore WL, Queen KL, et al. Biochemical determinants of growth sparing during neonatal deprivation or enhancement: ornithine decarboxylase, polyamines, and macromolecules in brain regions and heart. Pediatr Res. 1987;22:599–604.PubMedCrossRefGoogle Scholar
  36. 36.
    Brodsky VY, Pelouch V, Arefyeva AM, et al. Lack of proportionality between gene dosage and total muscle protein content in the rat heart. Int J Dev Biol. 1992;36:339–42.PubMedGoogle Scholar
  37. 37.
    Pelouch V, Kolar F, Milerova M, et al. Effect of preweanling nutritional state on the cardiac protein profile and functional performance of the rat heart. Mol Cell Biochem. 1997;177:221–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Dowell RT, Martin AF. Perinatal nutritional modification of weanling rat heart contractile protein. Am J Physiol Heart Circ Physiol. 1984;247:H967–72.Google Scholar
  39. 39.
    Rakusan K, Poupa O. Differences in capillary supply of hypertrophied and hyperplastic hearts. Cardiologia. 1966;49:293–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Neffgen F, Korecky B. Cellular hyperplasia and hypertrophy in cardiomegalies induced by anaemia in young and adult rats. Circulation Res. 1972;30:104–13.PubMedGoogle Scholar
  41. 41.
    Hollenberg M, Honbo N, Samorodin AJ. Effects of hypoxia on cardiac growth in neonatal rats. Am J Physiol. 1976;231:1445–50.PubMedGoogle Scholar
  42. 42.
    Wachtlova M, Mares V, Ostadal B. DNA synthesis in the ventricular myocardium of young rats exposed to intermittent high altitude (IHA) hypoxia. Virchows Arch B Cell Path. 1977;24:335–42.Google Scholar
  43. 43.
    Samanek M, Bass A, Ostadal B, et al. Effect of hypoxaemia on enzymes supplying myocardial energy in children with congenital heart disease. Int J Cardiol. 1989;25:265–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Fitzpatrick CM, Shi Y, Hutchins WC, et al. Cardioprotection in chronically hypoxic rabbits on exposure to normoxia: role of NOS and KATP channels. Am J Physiol Heart Circ Physiol. 2005;288:H62–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Ostadal B, Kolar F. Cardiac ischemia: from injury to protection. Boston: Kluwer Academic; 1999.Google Scholar
  46. 46.
    Ostadal B, Netuka I, Maly J, et al. Gender differences in cardiac ischemic injury and protection-experimental aspects. Exp Biol Med. 2009;234:1011–9.CrossRefGoogle Scholar
  47. 47.
    Riva A, Hearse DJ. Age-dependent changes in myocardial succeptibility to ischemic injury. Cardioscience. 2009;4:85–92.Google Scholar
  48. 48.
    Ostadalova I, Ostadal B, Kolar F, et al. Tolerance to ischemia and ischaemic preconditioning in neonatal rat heart. J Mol Cell Cardiol. 1998;30:857–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Baker EJ, Boerboom LE, Olinger GN, et al. Tolerance of the developing heart to ischemia: impact of hypoxemia from birth. Am J Physiol. 1998;268:H1165–73.Google Scholar
  50. 50.
    Hoerter J. Changes in the sensitivity to hypoxia and glucose deprivation in the isolated perfused rabbit heart during perinatal development. Pflugers Arch. 1976;363:1–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Julia P, Young PP, Buckberg GD, et al. Studies of myocardial protection in the immature heart. II. Evidence for importance of amino acid metabolism in tolerance to ischemia. J Thorac Cardiovasc Res. 1990;100:888–95.Google Scholar
  52. 52.
    Hohl CM. Effect of respiratory inhibition and ­ischemia on nucleotide metabolism in newborn swine ­cardiac myocytes. In: Ostadal B, Nagano M, Takeda N, Dhalla NS, editors. The developing heart. Philadelphia, PA: Lippincott; 1997. p. 393–406.Google Scholar
  53. 53.
    Vetter R, Studer R, Reinecke H, et al. Reciprocal changes in the postnatal expression of the sarcolemmal Na+-Ca2+-exchanger and SERCA2 in rat heart. J Mol Cell Cardiol. 1995;27:1689–701.PubMedCrossRefGoogle Scholar
  54. 54.
    Schagger H, Noack H, Halangk W, et al. Cytochrome c oxidase in developing rat heart. Enzymic properties and amino-terminal sequences suggest identity of the fetal heart and the adult liver isoform. Eur J Biochem. 1995;230:235–41.PubMedCrossRefGoogle Scholar
  55. 55.
    Drahota Z, Milerova M, Stieglerova A, et al. Developmental changes of cytochrome c oxidase and citrate synthase in rat heart homogenate. Physiol Res. 2004;53:119–22.PubMedGoogle Scholar
  56. 56.
    Di Lisa F, Bernardi P. Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem. 1998;184:379–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Di Lisa F, Bernardi P. Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition. Cardiovasc Res. 2006;66:222–32.CrossRefGoogle Scholar
  58. 58.
    Di Lisa F, Menabo R, Canton M, et al. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem. 2001;276:2571–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Milerova M, Charvatova Z, Skarka L, et al. Neonatal cardiac mitochondria and ischemia/reperfusion injury. Mol Cell Biochem. 2010;335:147–53.PubMedCrossRefGoogle Scholar
  60. 60.
    Heath D, Williams DR. High altitude medicine and pathology. Oxford: Oxford University Press; 1995.Google Scholar
  61. 61.
    Ostadal B, Kolar F. Cardiac adaptation to chronic high altitude hypoxia. Respir Physiol Neurobiol. 2007;158:224–36.PubMedCrossRefGoogle Scholar
  62. 62.
    Neckar J, Papousek F, Novakova O, et al. Cardioprotective effects of chronic hypoxia and ischaemic preconditioning are not additive. Basic Res Cardiol. 2002;97:161–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Neckar J, Szarszoi O, Koten L, et al. Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats. Cardiovasc Res. 2002;55:567–75.PubMedCrossRefGoogle Scholar
  64. 64.
    Asemu G, Papousek F, Ostadal B, et al. Adaptation to high altitude hypoxia protects the rat heart against ischemia-induced arrhythmias. Involvement of mitochondrial KATP channel. J Mol Cell Cardiol. 1999;31:821–31.CrossRefGoogle Scholar
  65. 65.
    Szarszoi O, Asemu G, Ostadal B, et al. Effects of melatonin on ischemia and reperfusion injury of the rat heart. Cardiovasc Drugs Ther. 2001;15:251–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Kolar F, Ostadal B. Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia. Physiol Res. 2004;53 Suppl 1:S3–13.PubMedGoogle Scholar
  67. 67.
    Ostadal B, Kolar F, Pelouch V, et al. Ontogenetic ­differences in cardiopulmonary adaptation to chronic hypoxia. Physiol Res. 1995;44:45–51.PubMedGoogle Scholar
  68. 68.
    Ostadalova I, Ostadal B, Jarkovska D, et al. Ischemic preconditioning in chronically hypoxic neonatal rat heart. Pediatr Res. 2002;52:561–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Ostadal B, Ostadalova I, Kolar F, et al. Ontogenetic development of cardiac tolerance to oxygen deprivation – possible mechanisms. Physiol Res. 2009;58 Suppl 2:S1–12.PubMedGoogle Scholar
  70. 70.
    Rakusan K, Chvojkova Z, Oliviero P, et al. ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats. Am J Physiol Heart Circ Physiol. 2007;292:H1–8.Google Scholar
  71. 71.
    Barker DJ. In utero programming of cardiovascular disease. Theriogenology. 2000;53:555–74.PubMedCrossRefGoogle Scholar
  72. 72.
    Sallout B, Walker M. The fetal origin of adult disease. J Obstet Gynaecol. 2003;23:555–60.PubMedCrossRefGoogle Scholar
  73. 73.
    Osmond C, Barker DJP, Winter PD, et al. Early growth and death from cardiovascular disease in women. BMJ. 1993;307:1519–24.PubMedCrossRefGoogle Scholar
  74. 74.
    Rich-Edwards JW, Stampfer MJ, Manson JE, et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ. 1997;315:396–400.PubMedGoogle Scholar
  75. 75.
    Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15  000 Swedish men and women born 1915–1929. BMJ. 1998;317:241–5.PubMedGoogle Scholar
  76. 76.
    Eriksson JG, Forsen T, Toumilehto J, et al. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ. 1999;318:427–31.PubMedGoogle Scholar
  77. 77.
    Crispi F, Bijnens B, Figueras F, et al. Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation. 2010;121:2427–36.PubMedCrossRefGoogle Scholar
  78. 78.
    Li G, Xiao Y, Estrella JL, et al. Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult heart. J Soc Gynecol Investig. 2003;10:265–74.PubMedCrossRefGoogle Scholar
  79. 79.
    Li G, Bae S, Zhang L. Effect of prenatal hypoxia on heat stress-mediated cardioprotection in adult rat heart. Am J Physiol Heart Circ Physiol. 2004;286:1712–9.CrossRefGoogle Scholar
  80. 80.
    Xu Y, Williams SJ, O’Brien D, et al. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J. 2006;20:1251–3.PubMedCrossRefGoogle Scholar
  81. 81.
    Peyronnet J, Dalmaz Y, Ehrstrom M. Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats. Pflugers Arch. 2002;443:858–65.PubMedCrossRefGoogle Scholar
  82. 82.
    Hampl V, Herget J. Perinatal hypoxia increases hypoxic pulmonary vasoconstriction in adult rats recovering from chronic exposure to hypoxia. Am Rev Respir Dis. 1990;142:619–24.PubMedGoogle Scholar
  83. 83.
    Hampl V, Bibova J, Ostadalova I, et al. Gender differences in the long-term effects of perinatal hypoxia on pulmonary circulation in rats. Am J Physiol Lung Cell Mol Physiol. 2003;285:L386–92.PubMedGoogle Scholar
  84. 84.
    Snoeckx LH, Cornelussen RN, Van Nieuwenhoven FA, et al. Heat shock proteins and cardiovascular pathophysiology. Physiol Rev. 2001;81:1461–97.PubMedGoogle Scholar
  85. 85.
    Di Lisa F. A female way to protect the heart. Say NO to calcium. Circ Res. 2006;98:298–300.PubMedCrossRefGoogle Scholar
  86. 86.
    Sun J, Picht E, Ginsburg KS, et al. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha 1 subunit and reduced ischemia-reperfusion injury. Circ Res. 2006;98:403–11.PubMedCrossRefGoogle Scholar
  87. 87.
    Johnson MS, Moore RL, Brown DA. Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blocade in rat. Am J Physiol Heart Circ Physiol. 2006;290:H2644–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Lee TM, Su SF, Tsai CC, et al. Cardioprotective effects of 17 beta-estradiol produced by activation of mitochondrial ATP-sensitive K+ channels in canine hearts. J Mol Cell Cardiol. 2000;32:1147–58.PubMedCrossRefGoogle Scholar
  89. 89.
    Bae S, Zhang L. Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Therap. 2005;315:1125–35.CrossRefGoogle Scholar
  90. 90.
    Cross HR, Murphy E, Steenbergen C. Ca2+ loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2002;283:H481–9.PubMedGoogle Scholar
  91. 91.
    Lagranha CJ, Deschamps A, Aponte A, et al. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ Res. 2010;106:1681–91.PubMedCrossRefGoogle Scholar
  92. 92.
    Murriel CL, Mochly-Rosen D. Opposing roles of delta and epsilon PKC in cardiac ischemia and reperfusion: targeting the apoptotic machinery. Arch Biochem Biophys. 2003;420:246–54.PubMedCrossRefGoogle Scholar
  93. 93.
    Kolar F, Novak F, Neckar J, et al. Role of protein kinases in chronic intermittent hypoxia-induced cardioprotection. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia. New York: Nova Science; 2009. p. 213–30.Google Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Bohuslav Ostadal
    • 1
    • 2
  • I. Ostadalova
    • 3
    • 2
  • F. Kolar
    • 3
    • 2
  • I. Netuka
    • 1
    • 4
  • O. Szarszoi
    • 5
  1. 1.Centre for Cardiovascular ResearchPragueCzech Republic
  2. 2.Institute of Physiology, Academy of Sciences of the Czech RepublicPragueCzech Republic
  3. 3.Centre for Cardiovascular Research, Academy of Sciences of the Czech RepublicPragueCzech Republic
  4. 4.Institute for Clinical and Experimental MedicinePragueCzech Republic
  5. 5.Centre for Cardiovascular Research, Institute for Clinical and Experimental MedicinePragueCzech Republic

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