Advertisement

Intermittent Hypoxia and Atherosclerosis

  • Demet TekinEmail author
  • Elisa Chong
  • Lei Xi
Chapter

Abstract

Atherosclerosis is a common pathologic condition that is affecting millions of people in their large and small arteries, including the aorta, coronary, and cerebral arteries. Atherosclerotic lesions are characterized by focal thickening of the vascular tunica intima, through the accumulation of fatty deposits, platelets, and leukocytes in the endothelial cell layer, which eventually form the fatty streaks and plaques inside vascular walls. The subsequent ulceration and rupture of plaques could trigger the formation of thrombi that may partially or completely obstruct blood circulation and cause devastating consequences impairing the function and survival of vital organs. Therefore, atherosclerosis represents a distinguished basis of cardiac, cerebral, and peripheral vascular diseases. This chapter is aimed at providing a comprehensive and non-biased overview on the updated evidence of both detrimental and beneficial effects of intermittent hypoxia in the pathological process of atherosclerosis. Collectively, there is a remarkably abundant body of evidence for an atherogenic role played by chronic and severe intermittent hypoxia. On the other hand, a number of studies originated predominantly by Russian/Ukrainian scientists also demonstrated paradoxical anti-atherosclerosis prophylactic and therapeutic effects, which could be elicited by some well-controlled training/conditioning regimens with often mild or moderate levels of intermittent hypoxia. Considering these most updated evidence and divergent points of view, we have further discussed the possible molecular signaling pathways for both detrimental and protective mechanisms of IH. Nevertheless, many seemingly controversial areas require further investigations, which will undoubtedly bring new insights into the fundamental issue of prevention and treatment of atherosclerosis-associated ­cardiovascular diseases.

Keywords

Nitric Oxide Vascular Endothelial Growth Factor Nitric Oxide Synthases Obstructive Sleep Apnea Continuous Positive Airway Pressure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

APOE

Apolipoprotein E

COX-2

Cyclooxygenase-2

CPAP

Continuous positive airway pressure

ELAM

Endothelial-leukocyte adhesion molecule

eNOS

Endothelial nitric oxide synthase

EPCs

Endothelial progenitor cells

EPO

Erythropoietin

FFA

Free fatty acid

FGF

Fibroblast growth factor

FMD

Flow-mediated dilation

HDL

High-density lipoprotein

HIF-1

Hypoxia inducible factor 1

ICAM

Intercellular adhesion molecule

IGF-1

Insulin-like growth factor

IH

Intermittent hypoxia

IHT

Intermittent hypoxia training

IL-6

Interleukin 6

IMT

Intima–media thickness

iNOS

Inducible nitric oxide synthase

LDL

Low-density lipoprotein

LTB4

Leukotriene B4

MCP-1

Monocyte chemotactic protein 1

NADPH

Nicotinamide adenine dinucleotide phosphate

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

NOS

Nitric oxide synthase

OSA

Obstructive sleep apnea

PAI-1

Plasminogen activator inhibitor 1

PDGF

Platelet-derived growth factor

PMNs

Polymorphonuclear leukocytes

RDI

Respiratory disturbance index

ROS

Reactive oxygen species

SCD-1

Stearoyl coenzyme A desaturase 1

SMCs

Smooth muscle cells

SREBP

Sterol regulatory element-binding protein

TF

Tissue factor

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor-alpha

TRLP

Triglyceride-rich lipoprotein

VCAM

Vascular cell adhesion molecule

VEGF

Vascular endothelial growth factor

VLDL

Very-low-density lipoprotein

Notes

Acknowledgments

We like to thank Prof. Tatiana V. Serebrovskaya for sharing her vast knowledge of the relevant studies published in Russian and Ukrainian languages, which enabled us to provide a more balanced presentation of the less known and insufficiently recognized evidence for the beneficial role of intermittent hypoxia in limiting the atherogenic factors.

References

  1. 1.
    Al Lawati NM, Patel SR, Ayas NT. Epidemiology, risk factors, and consequences of obstructive sleep apnea and short sleep duration. Prog Cardiovasc Dis. 2009;51:285–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Aleshin IA, Kots IaI, Tverdokhlib VP, et al. The nondrug treatment of hypertension patients by their adaptation to periodic hypoxia in a barochamber. Ter Arkh. 1993;65:23–9 [In Russian].PubMedGoogle Scholar
  3. 3.
    Alonso-Fernández A, García-Río F, Arias MA, et al. Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax. 2009;64:581–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Arnaud C, Dematteis M, Pepin JL, et al. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis. Semin Immunopathol. 2009;31:113–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Barceló A, Barbé F, de la Peña M, et al. Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. Eur Respir J. 2006;27:756–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Belaidi E, Beguin PC, Levy P, et al. Prevention of HIF-1 activation and iNOS gene targeting by low-dose cadmium results in loss of myocardial hypoxic preconditioning in the rat. Am J Physiol Heart Circ Physiol. 2008;294:H901–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Berger S, Lavie L. Endothelial progenitor cells in cardiovascular disease and hypoxia-potential implications to obstructive sleep apnea. Transl Res. 2011;158:1–13.PubMedCrossRefGoogle Scholar
  8. 8.
    Berglund B, Aulin KP, Wide L. Effect of short-term and intermittent normobaric hypoxia on endogenous erythropoietin isoforms. Scand J Med Sci Sports. 2003;13:124–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Bertuglia S. Intermittent hypoxia modulates nitric oxide-dependent vasodilation and capillary perfusion during ischemia-reperfusion-induced damage. Am J Physiol Heart Circ Physiol. 2008;294:H1914–22.PubMedCrossRefGoogle Scholar
  10. 10.
    Birot OJ, Peinnequin A, Simler N, et al. Vascular endothelial growth factor expression in heart of rats exposed to hypobaric hypoxia: differential response between mRNA and protein. J Cell Physiol. 2004;200:107–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364:1746–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Boström P, Magnusson B, Svensson PA, et al. Hypoxia converts human macrophages into triglyceride-loaded foam cells. Arterioscler Thromb Vasc Biol. 2006;26:1871–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Brugniaux JV, Pialoux V, Foster GE, et al. Effects of intermittent hypoxia on erythropoietin, soluble erythropoietin receptor and ventilation in humans. Eur Respir J. 2011;37:880–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Buchner NJ, Quack I, Stegbauer J, et al. Treatment of obstructive sleep apnea reduces arterial stiffness. Sleep Breath. 2012;16(1):123–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Buemi M, Allegra A, Corica F, et al. Does erythropoietin administration affect progression of atherosclerosis in Watanabe heritable hyperlipaemic rabbits? Nephrol Dial Transplant. 1998;13:2706–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Cahan C, Decker MJ, Arnold JL, et al. Erythropoietin levels with treatment of obstructive sleep apnea. J Appl Physiol. 1995;79:1278–85.PubMedGoogle Scholar
  17. 17.
    Cataldi A, Bianchi G, Rapino C, et al. Molecular and morphological modifications occurring in rat heart exposed to intermittent hypoxia: role for protein kinase C α. Exp Gerontol. 2004;39:395–405.PubMedCrossRefGoogle Scholar
  18. 18.
    Chello M, Anselmi A, Spadaccio C, et al. Simvastatin increases neutrophil apoptosis and reduces inflammatory reaction after coronary surgery. Ann Thorac Surg. 2007;83:1374–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen XY, Zeng YM, Huang ZY, et al. Effect of chronic intermittent hypoxia on hypoxia inducible factor-1 alpha in mice. Zhonghua Jie He He Hu Xi Za Zhi. 2005;28:93–6 [In Chinese].PubMedGoogle Scholar
  21. 21.
    Chen CY, Tsai YL, Kao CL, et al. Effect of mild intermittent hypoxia on glucose tolerance, muscle morphology and AMPK-PGC-1alpha signaling. Chin J Physiol. 2010;53:62–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Corretti MC, Anderson TJ, Benjamin EJ, et al. International brachial artery reactivity task force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Corwin EJ, Cannon JG. Cardiovascular system: conditions of disease or injury: atherosclerosis. In: Corwin EJ, editor. Handbook of pathophysiology. 3rd ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkin; 2008.Google Scholar
  24. 24.
    Desai A, Zhao Y, Lankford HA, et al. Nitric oxide suppresses EPO-induced monocyte chemoattractant protein-1 in endothelial cells: implications for atherogenesis in chronic renal disease. Lab Invest. 2006;86:369–79.PubMedCrossRefGoogle Scholar
  25. 25.
    Dhar-Mascareño M, Cárcamo JM, Golde DW. Hypoxia-reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C. Free Radic Biol Med. 2005;38:1311–22.PubMedCrossRefGoogle Scholar
  26. 26.
    Ding HL, Zhu HF, Dong JW, et al. Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury. Acta Pharmacol Sin. 2005;26:315–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Dopp JM, Philippi NR, Marcus NJ, et al. Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats. Respiration. 2011;82:458–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Drager LF, Bortolotto LA, Lorenzi MC, et al. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2005;172:613–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Drager LF, Bortolotto LA, Figueiredo AC, et al. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176:706–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Drager LF, Bortolotto LA, Krieger EM, et al. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension. 2009;53:64–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Drager LF, Jun J, Polotsky VY. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab. 2010;24:843–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Drager LF, Li J, Shin MK et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J 2012;33:783–90.Google Scholar
  33. 33.
    Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med. 2002;165:934–9.PubMedGoogle Scholar
  34. 34.
    Dyugovskaya L, Lavie P, Lavie L. Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci. 2005;1051:340–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Dyugovskaya L, Polyakov A, Lavie P, et al. Delayed neutrophil apoptosis in patients with sleep apnea. Am J Respir Crit Care Med. 2008;177:544–54.PubMedCrossRefGoogle Scholar
  36. 36.
    El Solh AA, Akinnusi ME, Baddoura FH, et al. Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. Am J Respir Crit Care Med. 2007;175:1186–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Farré R, Montserrat JM, Navajas D. Morbidity due to obstructive sleep apnea: insights from animal models. Curr Opin Pulm Med. 2008;14:530–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Faure P, Tamisier R, Baguet JP, et al. Impairment of serum albumin antioxidant properties in obstructive sleep apnoea syndrome. Eur Respir J. 2008;31:1046–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Feng J, Zhang D, Chen B. Endothelial mechanisms of endothelial dysfunction in patients with obstructive sleep apnea. Sleep Breath 2012;16:283–94.Google Scholar
  40. 40.
    Fitzpatrick SF, Tambuwala MM, Bruning U, et al. An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol. 2011;186:1091–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Foresi A, Leone C, Olivieri D, et al. Alveolar-derived exhaled nitric oxide is reduced in obstructive sleep apnea syndrome. Chest. 2007;132:860–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Forsythe JA, Jiang B-H, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.PubMedGoogle Scholar
  43. 43.
    Foster GE, Poulin MJ, Hanly PJ. Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp Physiol. 2007;92:51–65.PubMedCrossRefGoogle Scholar
  44. 44.
    Foster GE, Brugniaux JV, Pialoux V, et al. Cardiovascular and cerebrovascular responses to acute hypoxia following exposure to intermittent hypoxia in healthy humans. J Physiol. 2009;587:3287–99.PubMedCrossRefGoogle Scholar
  45. 45.
    Fujiwara N, Nakamura T, Sato E, et al. Renovascular protective effects of erythropoietin in patients with chronic kidney disease. Intern Med. 2011;50:1929–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110:364–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Glaus TM, Grenacher B, Koch D, et al. High altitude training of dogs results in elevated erythropoietin and endothelin-1 serum levels. Comp Biochem Physiol A Mol Integr Physiol. 2004;138:355–61.PubMedCrossRefGoogle Scholar
  48. 48.
    Gore CJ, Rodríguez FA, Truijens MJ, et al. Increased serum erythropoietin but not red cell production after 4 wk of intermittent hypobaric hypoxia (4,000–5,500 m). J Appl Physiol. 2006;101:1386–93.PubMedCrossRefGoogle Scholar
  49. 49.
    Gozal D, Lipton AJ, Jones KL. Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea. Sleep. 2002;25:59–65.PubMedGoogle Scholar
  50. 50.
    Grebe M, Eisele HJ, Weissmann N, et al. Antioxidant vitamin C improves endothelial function in obstructive sleep apnea. Am J Respir Crit Care Med. 2006;173:897–901.PubMedCrossRefGoogle Scholar
  51. 51.
    Griendling KK, Harrison DG, Alexander RW. Biology of the vessel wall: endothelial dysfunction and vascular smooth muscle abnormalities. In: Hurst JW, Fuster V, Walsh RA, editors. Hurst’s the heart. 13th ed. New York: McGraw-Hill Medical; 2011.Google Scholar
  52. 52.
    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Heinicke K, Prommer N, Cajigal J, et al. Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man. Eur J Appl Physiol. 2003;88:535–43.PubMedCrossRefGoogle Scholar
  54. 54.
    Helin P, Lorenzen I, Garbarsch C, et al. Arteriosclerosis and hypoxia. 2. Biochemical changes in mucopolysaccharides and collagen of rabbit aorta induced by systemic hypoxia. J Atheroscler Res. 1969;9:295–304.PubMedCrossRefGoogle Scholar
  55. 55.
    Hoffstein V, Herridge M, Mateika S, et al. Hematocrit levels in sleep apnea. Chest. 1994;106:787–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Inoue M, Itoh H, Ueda M, et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998;98:2108–16.PubMedCrossRefGoogle Scholar
  57. 57.
    Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;162:2166–71.PubMedGoogle Scholar
  58. 58.
    Ip MS, Tse HF, Lam B, et al. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;169:348–53.PubMedCrossRefGoogle Scholar
  59. 59.
    Ishii M, Iwamoto T, Nagai A, et al. Polycythemia and changes in erythropoietin concentration in rats exposed to intermittent hypoxia. Adv Exp Med Biol. 2010;662:121–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117:2270–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Johnson BD, Kip KE, Marroquin OC, et al. Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004;109:726–32.PubMedCrossRefGoogle Scholar
  62. 62.
    Jun J, Reinke C, Bedja D, et al. Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis. 2010;209:381–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Juonala M, Viikari JS, Alfthan G, et al. Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study. Circulation. 2007;116:1367–73.PubMedCrossRefGoogle Scholar
  64. 64.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95.PubMedCrossRefGoogle Scholar
  65. 65.
    Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000;102:2607–10.PubMedCrossRefGoogle Scholar
  66. 66.
    Kent BD, Ryan S, McNicholas WT. Obstructive sleep apnea and inflammation: relationship to cardiovascular co-morbidity. Respir Physiol Neurobiol. 2011;178:475–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Kepez A, Niksarlıoğlu EY, Hazırolan T, et al. Evaluation of association between obstructive sleep apnea and coronary risk scores predicted by tomographic coronary calcium scoring in asymptomatic patients. Anadolu Kardiyol Derg. 2011;11:428–35.PubMedGoogle Scholar
  68. 68.
    Khayat R, Patt B, Hayes Jr D. Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease. Heart Fail Rev. 2009;14:143–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Kitaev MI, Aĭtbaev KA, Liamtsev VT. Effect of hypoxic hypoxia on development of atherosclerosis in rabbits. Aviakosm Ekolog Med. 1999;33(5):54–7 [In Russian].PubMedGoogle Scholar
  70. 70.
    Knaupp W, Khilnani S, Sherwood J, et al. Erythropoietin response to acute normobaric hypoxia in humans. J Appl Physiol. 1992;73:837–40.PubMedGoogle Scholar
  71. 71.
    Kraiczi H, Caidahl K, Samuelsson A, et al. Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep. Chest. 2001;119:1085–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Lau AK, Chaufour X, McLachlan C, et al. Intimal thickening after arterial balloon injury is increased by intermittent repetitive hypoxia, but intermittent repetitive hyperoxia is not protective. Atherosclerosis. 2006;185:254–63.PubMedCrossRefGoogle Scholar
  73. 73.
    Lavie L. Intermittent hypoxia: the culprit of oxidative stress, vascular inflammation and dyslipidemia in obstructive sleep apnea. Expert Rev Respir Med. 2008;2:75–84.PubMedCrossRefGoogle Scholar
  74. 74.
    Lavie L. Oxidative stress - a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis. 2009;51:303–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Lavie P, Lavie L. Unexpected survival advantage in elderly people with moderate sleep apnoea. J Sleep Res. 2009;18:397–403.PubMedCrossRefGoogle Scholar
  76. 76.
    Lavie L, Kraiczi H, Hefetz A, et al. Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med. 2002;165:1624–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Lavie L, Dyugovskaya L, Lavie P. Sleep-apnea-related intermittent hypoxia and atherogenesis: adhesion molecules and monocytes/endothelial cells interactions. Atherosclerosis. 2005;183:183–4.PubMedCrossRefGoogle Scholar
  78. 78.
    Lévy P, Pépin JL, Arnaud C, et al. Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis. 2009;51:400–10.PubMedCrossRefGoogle Scholar
  79. 79.
    Li J, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res. 2005;97:698–706.PubMedCrossRefGoogle Scholar
  80. 80.
    Li J, Nanayakkara A, Jun J, et al. Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia. Physiol Genomics. 2007;31:273–80.PubMedCrossRefGoogle Scholar
  81. 81.
    Li J, Savransky V, Nanayakkara A, et al. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol. 2007;102:557–63.PubMedCrossRefGoogle Scholar
  82. 82.
    Li RC, Haribabu B, Mathis SP, et al. Leukotriene B4 receptor-1 mediates intermittent hypoxia-Induced atherogenesis. Am J Respir Crit Care Med. 2011;184:124–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Lu KY, Ching LC, Su KH, et al. Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha. Circulation. 2010;121:1828–37.PubMedCrossRefGoogle Scholar
  84. 84.
    Lyamina NP, Lyamina SV, Senchiknin VN, et al. Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension. J Hypertens. 2011;29:2265–72.PubMedCrossRefGoogle Scholar
  85. 85.
    Manukhina EB, Mashina SYu, Smirin BV, et al. Role of nitric oxide in adaptation to hypoxia and adaptive defense. Physiol Res. 2000;49:89–97.PubMedGoogle Scholar
  86. 86.
    Manukhina EB, Jasti D, Vanin AF, et al. Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats. Exp Biol Med. 2011;236:867–73.CrossRefGoogle Scholar
  87. 87.
    Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365:1046–53.PubMedGoogle Scholar
  88. 88.
    McGuire M, Bradford A. Chronic intermittent hypoxia increases haematocrit and causes right ventricular hypertrophy in the rat. Respir Physiol. 1999;117:53–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Mescher AL. The circulatory system: tissues of the vascular wall and structural plan of blood vessels. In: Junqueira LCU, Mescher AL, editors. Junqueira’s basic histology: text & atlas. 12th ed. New York: McGraw-Hill Medical; 2010.Google Scholar
  90. 90.
    Minoguchi K, Yokoe T, Tazaki T, et al. Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med. 2005;172:625–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Minvaleev RS. A comparison of rate of human lipid profile changes at moderate altitude. Fiziol Cheloveka. 2011;37:103–8 [In Russian].PubMedGoogle Scholar
  92. 92.
    Mitrovic I. Cardiovascular disorders: vascular disease. In: McPhee SJ, Hammer GD, editors. Pathophysiology of disease: an introduction to clinical medicine. 6th ed. New York: McGraw-Hill Medical; 2010.Google Scholar
  93. 93.
    Monneret D, Pepin JL, Godin-Ribuot D, et al. Association of urinary 15-F2t-isoprostane level with oxygen desaturation and carotid intima-media thickness in nonobese sleep apnea patients. Free Radic Biol Med. 2010;48:619–25.PubMedCrossRefGoogle Scholar
  94. 94.
    Morgan BJ. Vascular consequences of intermittent hypoxia. Adv Exp Med Biol. 2007;618:69–84.PubMedCrossRefGoogle Scholar
  95. 95.
    Naito R, Sakakura K, Kasai T et al. Aortic dissection is associated with intermittent hypoxia and re-oxygenation. Heart Vessels 2011 May 15. [Epub ahead of print]Google Scholar
  96. 96.
    Newman AB, Nieto FJ, Guidry U, et al. Sleep Heart Health Study Research Group. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol. 2001;154:50–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000;283:1829–36.PubMedCrossRefGoogle Scholar
  98. 98.
    Nieto FJ, Herrington DM, Redline S, et al. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Respir Crit Care Med. 2004;169:354–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Pawlak K, Pawlak D, Mysliwiec M. Long-term erythropoietin therapy decreases CC-chemokine levels and intima-media thickness in hemodialyzed patients. Am J Nephrol. 2006;26:497–502.PubMedCrossRefGoogle Scholar
  100. 100.
    Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J. 1999;14:179–84.PubMedCrossRefGoogle Scholar
  101. 101.
    Perry JC, D’Almeida V, Souza FG, et al. Consequences of subchronic and chronic exposure to intermittent hypoxia and sleep deprivation on cardiovascular risk factors in rats. Respir Physiol Neurobiol. 2007;156:250–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Philippi NR, Bird CE, Marcus NJ, et al. Time course of intermittent hypoxia-induced impairments in resistance artery structure and function. Respir Physiol Neurobiol. 2010;170:157–63.PubMedCrossRefGoogle Scholar
  103. 103.
    Phillips SA, Olson EB, Morgan BJ, et al. Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol. 2004;286:H388–93.PubMedCrossRefGoogle Scholar
  104. 104.
    Portnychenko AH, Rozova KV, Vasylenko MI, et al. Age-dependent differences of the ultrastructural changes in the myocardium after hypoxical preconditioning and ischemia-reperfusion of the isolated heart in rats. Fiziol Zh. 2007;53:27–34 [In Ukrainian].PubMedGoogle Scholar
  105. 105.
    Prysiazhna OD, Kotsiuruba AV, Talanov SO, et al. Normalizing effect of intermittent hypoxic training on the function of endothelium in experimental diabetes mellitus. Fiziol Zh. 2007;53(2):3–7 [In Ukrainian].Google Scholar
  106. 106.
    Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med. 2009;6:e1000132.PubMedCrossRefGoogle Scholar
  107. 107.
    Qin L, Xiang Y, Song Z, et al. Erythropoietin as a possible mechanism for the effects of intermittent hypoxia on bodyweight, serum glucose and leptin in mice. Regul Pept. 2010;165:168–73.PubMedCrossRefGoogle Scholar
  108. 108.
    Robinson GV, Pepperell JC, Segal HC, et al. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomized controlled trials. Thorax. 2004;59:777–82.PubMedCrossRefGoogle Scholar
  109. 109.
    Rodríguez FA, Ventura JL, Casas M. Erythropoietin acute reaction and haematological adaptations to short, intermittent hypobaric hypoxia. Eur J Appl Physiol. 2000;82:170–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Ropert S, Vignaux O, Mir O, et al. VEGF pathway inhibition by anticancer agent sunitinib and susceptibility to atherosclerosis plaque disruption. Invest New Drugs. 2011;29:1497–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Ross R. Cell biology of atherosclerosis. Annu Rev Physiol. 1995;57:791–804.PubMedCrossRefGoogle Scholar
  112. 112.
    Ryan S, McNicholas WT. Intermittent hypoxia and activation of inflammatory molecular pathways in OSAS. Arch Physiol Biochem. 2008;114:261–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Ryan S, McNicholas WT. Inflammatory cardiovascular risk markers in obstructive sleep apnoea syndrome. Cardiovasc Hematol Agents Med Chem. 2009;7:76–81.PubMedCrossRefGoogle Scholar
  114. 114.
    Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax. 2009;64:631–6.PubMedGoogle Scholar
  115. 115.
    Ryou MG, Sun J, Oguayo KN, et al. Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion. Exp Biol Med. 2008;233:766–74.CrossRefGoogle Scholar
  116. 116.
    Sajkov D, Cowie RJ, Thornton AT, et al. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1994;149:416–22.PubMedGoogle Scholar
  117. 117.
    Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med. 2007;175:1290–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Savransky V, Jun J, Li J, et al. Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res. 2008;103:1173–80.PubMedCrossRefGoogle Scholar
  119. 119.
    Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med. 2000;162:566–70.PubMedGoogle Scholar
  120. 120.
    Semenza GL. O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J Appl Physiol. 2004;96:1173–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Shah NA, Yaggi HK, Concato J, et al. Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath. 2010;14:131–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA. 2003;290:1906–14.PubMedCrossRefGoogle Scholar
  123. 123.
    Sugamura K, Keaney Jr JF. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med. 2011;51:978–92.PubMedCrossRefGoogle Scholar
  124. 124.
    Svatikova A, Wolk R, Shamsuzzaman AS, et al. Serum amyloid a in obstructive sleep apnea. Circulation. 2003;108:1451–4.PubMedCrossRefGoogle Scholar
  125. 125.
    Szabóová E, Tomori Z, Donic V, et al. Sleep apnoea inducing hypoxemia is associated with early signs of carotid atherosclerosis in males. Respir Physiol Neurobiol. 2007;155:121–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Tekin D, Dursun AD, Xi L. Hypoxia inducible factor 1 (HIF-1) and cardioprotection. Acta Pharmacol Sin. 2010;31:1085–94.PubMedCrossRefGoogle Scholar
  127. 127.
    Tekin D, Dursun AD, Baştuğ M, et al. The effects of acute and intermittent hypoxia on the expressions of HIF-1α and VEGF in the left and right ventricles of the rabbit heart. Anadolu Kardiyol Derg. 2011;11:379–85.PubMedGoogle Scholar
  128. 128.
    Tin’kov AN, Aksenov VA. Effects of intermittent hypobaric hypoxia on blood lipid concentrations in male coronary heart disease patients. High Alt Med Biol. 2002;3:277–82.PubMedCrossRefGoogle Scholar
  129. 129.
    Vinnikov D, Brimkulov N, Redding-Jones R, et al. Exhaled nitric oxide is reduced upon chronic intermittent hypoxia exposure in well-acclimatized mine workers. Respir Physiol Neurobiol. 2011;175:261–4.PubMedCrossRefGoogle Scholar
  130. 130.
    von Känel R, Loredo JS, Ancoli-Israel S, et al. Association between polysomnographic measures of disrupted sleep and prothrombotic factors. Chest. 2007;131:733–9.CrossRefGoogle Scholar
  131. 131.
    Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007;49:1625–31.PubMedCrossRefGoogle Scholar
  132. 132.
    Wang JS, Chen LY, Fu LL, et al. Effects of moderate and severe intermittent hypoxia on vascular endothelial function and haemodynamic control in sedentary men. Eur J Appl Physiol. 2007;100:127–35.PubMedCrossRefGoogle Scholar
  133. 133.
    Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation. 2003;108:9–12.PubMedCrossRefGoogle Scholar
  134. 134.
    Xi L, Tekin D, Gursoy E, et al. Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. Am J Physiol Heart Circ Physiol. 2002;283:H5–12.PubMedGoogle Scholar
  135. 135.
    Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034–41.PubMedCrossRefGoogle Scholar
  136. 136.
    Yamauchi M, Kimura H. Oxidative stress in obstructive sleep apnea: putative pathways to the cardiovascular complications. Antioxid Redox Signal. 2008;10:755–68.PubMedCrossRefGoogle Scholar
  137. 137.
    Young T, Palta M, Dempsey J, et al. The occurrence of sleep-­disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.PubMedCrossRefGoogle Scholar
  138. 138.
    Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165:1217–39.PubMedCrossRefGoogle Scholar
  139. 139.
    Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008;31:1071–8.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  1. 1.Department of Physiology, School of MedicineAnkara UniversityAnkaraTurkey
  2. 2.Division of Cardiology, School of MedicineVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations