Benefits and Risks of Manipulating the HIF Hydroxylase Pathway in Ischemic Heart Disease

  • Tammie Bishop
  • Peter J. Ratcliffe


Ischemic heart disease is a major cause of morbidity and mortality in the Western world. It occurs when oxygen delivery cannot meet the metabolic needs of the heart, as observed in patients with stable coronary artery disease as well as those experiencing acute myocardial infarction. Although conditions leading to myocardial injury have been well studied, and physical means of revascularization by stenting or coronary bypass surgery are well developed, there remains a need to define treatments that limit damage in the acute phase or promote revascularization by medical means. In particular, mechanisms that preserve cellular function during ischemia remain poorly understood.


Ischemic Insult Stable Coronary Artery Disease Prolyl Hydroxylase Domain Minimize Tissue Damage Intraventricular Infusion 
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  1. 1.
    Kaelin Jr WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.PubMedCrossRefGoogle Scholar
  2. 2.
    Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108:79–85.PubMedCrossRefGoogle Scholar
  3. 3.
    Cai Z, Zhong H, Bosch-Marce M, et al. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovasc Res. 2008;77:463–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Eckle T, Kohler D, Lehmann R, El Kasmi K, Eltzschig HK. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation. 2008;118:166–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Kido M, Du L, Sullivan CC, et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol. 2005;46:2116–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Elson DA, Thurston G, Huang LE, et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev. 2001;15:2520–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102:898–901.PubMedGoogle Scholar
  8. 8.
    Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med. 2000;6:1102–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Kant R, Diwan V, Jaggi AS, Singh N, Singh D. Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases. Mol Cell Biochem. 2008;312:25–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Dendorfer A, Heidbreder M, Hellwig-Burgel T, Johren O, Qadri F, Dominiak P. Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals. Free Radic Biol Med. 2005;38:117–24.PubMedCrossRefGoogle Scholar
  11. 11.
    Xi L, Taher M, Yin C, Salloum F, Kukreja RC. Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1alpha and AP-1 and iNOS signaling. Am J Physiol Heart Circ Physiol. 2004;287:H2369–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhao HX, Wang XL, Wang YH, et al. Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1alpha. Basic Res Cardiol. 2010;105:109–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Ockaili R, Natarajan R, Salloum F, et al. HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation. Am J Physiol Heart Circ Physiol. 2005;289:H542–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Philipp S, Jurgensen JS, Fielitz J, et al. Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats. Eur J Heart Fail. 2006;8:347–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22:4082–90.PubMedCrossRefGoogle Scholar
  16. 16.
    Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler 3rd AA. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res. 2006;98:133–40.PubMedCrossRefGoogle Scholar
  17. 17.
    Natarajan R, Salloum FN, Fisher BJ, Ownby ED, Kukreja RC, Fowler 3rd AA. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. Am J Physiol Heart Circ Physiol. 2007;293:H1571–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Huang M, Chan DA, Jia F, et al. Short hairpin RNA interference therapy for ischemic heart disease. Circulation. 2008;118:S226–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH. Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol. 2006;26:8336–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Hyvarinen J, Hassinen IE, Sormunen R, et al. Hearts of hypoxia-inducible factor prolyl 4-hydroxylase-2 hypomorphic mice show protection against acute ischemia-reperfusion injury. J Biol Chem. 2010;285:13646–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Adluri RS, Thirunavukkarasu M, Dunna NR, et al. Disruption of HIF-prolyl hydroxylase-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through HIF-1alpha transcription factor and its target genes in mice. Antiox Redox Signal 2011;15:1789–97.Google Scholar
  22. 22.
    Aragones J, Schneider M, Van Geyte K, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008;40:170–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Schneider M, Van Geyte K, Fraisl P, et al. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology. 2010;138:1143–54. e1–2.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang Q, Gu J, Li L, et al. Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell. 2009;16:413–24.PubMedCrossRefGoogle Scholar
  25. 25.
    Moslehi J, Minamishima YA, Shi J, et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation. 2010;122:1004–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Bekeredjian R, Walton CB, MacCannell KA, et al. Conditional HIF-1alpha expression produces a reversible cardiomyopathy. PLoS One. 2010;5:e11693.PubMedCrossRefGoogle Scholar
  27. 27.
    Morin Y, Daniel P. Quebec beer-drinkers’ cardiomyopathy: etiological considerations. Can Med Assoc J. 1967;97:926–8.PubMedGoogle Scholar
  28. 28.
    Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin Jr WG. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111:3236–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin Jr WG. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29:5729–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Takeda K, Aguila HL, Parikh NS, et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood. 2008;111:3229–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Takeda K, Cowan A, Fong GH. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation. 2007;116:774–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Bishop T, Gallagher D, Pascual A, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol. 2008;28:3386–400.PubMedCrossRefGoogle Scholar
  33. 33.
    Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood. 2008;112:919–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Gnarra JR, Ward JM, Porter FD, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci USA. 1997;94:9102–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Lei L, Mason S, Liu D, et al. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol. 2008;28:3790–803.PubMedCrossRefGoogle Scholar
  36. 36.
    Willam C, Maxwell PH, Nichols L, et al. HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation. J Mol Cell Cardiol. 2006;41:68–77.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285:H579–88.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2012

Authors and Affiliations

  1. 1.Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK

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