Korean J Physiol Pharmacol.  2013 Apr;17(2):111-120. 10.4196/kjpp.2013.17.2.111.

Prolyl 4 Hydroxylase: A Critical Target in the Pathophysiology of Diseases

• Kant R
• Bali A
• Singh N
• Jaggi AS

• KMID: 1429381
• DOI: http://doi.org/10.4196/kjpp.2013.17.2.111

Abstract

Prolyl 4 hydroxylases (P4H) are iron- and 2-oxoglutamate-dependent dioxygenase enzymes and hypoxia-inducible transcription factor (HIF)-P4Hs play a critical role in the regulating oxygen homeostasis in the local tissues as well in the systemic circulation. Over a period of time, a number of prolyl hydroxylase inhibitors and activators have been developed. By employing the pharmacological tools and transgenic knock out animals, the critical role of these enzymes has been established in the pathophysiology of number of diseases including myocardial infarction, congestive heart failure, stroke, neurodegeneration, inflammatory disease, respiratory diseases, retinopathy and others. The present review discusses the different aspects of these enzymes including their pathophysiological role in disease development.

Keyword

Hypoxia inducible factor; Inflammation; Ischemia; Prolyl hydroxylase

MeSH Terms

Animals
Heart Failure
Homeostasis
Inflammation
Ischemia
Mixed Function Oxygenases
Myocardial Infarction
Oxygen
Procollagen-Proline Dioxygenase
Stroke
Transcription Factors
Mixed Function Oxygenases
Oxygen
Procollagen-Proline Dioxygenase
Transcription Factors

Figure

• 

  Fig. 1 The effects of O2 changes (hypoxia and normoxia) on the fate of HIF-1α and mechanism of HIF-induced transcriptional changes.

• 

  Fig. 2 Therapeutic implications of HIF-P4H inhibitors in different diseases.

Reference

1. Bao W, Qin P, Needle S, Erickson-Miller CL, Duffy KJ, Ariazi JL, Zhao S, Olzinski AR, Behm DJ, Pipes GC, Jucker BM, Hu E, Lepore JJ, Willette RN. Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat. J Cardiovasc Pharmacol. 2010; 56:147–155. PMID: 20714241.

2. Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med. 2001; 33:7–21. PMID: 11310942.

3. Johnstone IL. Cuticle collagen genes. Expression in Caenorhabditis elegans. Trends Genet. 2000; 16:21–27. PMID: 10637627.

4. Myllyharju J, Kukkola L, Winter AD, Page AP. The exoskeleton collagens in Caenorhabditis elegans are modified by prolyl 4-hydroxylases with unique combinations of subunits. J Biol Chem. 2002; 277:29187–29196. PMID: 12036960.

5. Annunen P, Koivunen P, Kivirikko KI. Cloning of the alpha subunit of prolyl 4-hydroxylase from Drosophila and expression and characterization of the corresponding enzyme tetramer with some unique properties. J Biol Chem. 1999; 274:6790–6796. PMID: 10037780.

6. Merriweather A, Guenzler V, Brenner M, Unnasch TR. Characterization and expression of enzymatically active recombinant filarial prolyl 4-hydroxylase. Mol Biochem Parasitol. 2001; 116:185–197. PMID: 11522351.

7. Winter AD, Myllyharju J, Page AP. A hypodermally expressed prolyl 4-hydroxylase from the filarial nematode Brugia malayi is soluble and active in the absence of protein disulfide isomerase. J Biol Chem. 2003; 278:2554–2562. PMID: 12417582.

8. Kaska DD, Myllylä R, Günzler V, Gibor A, Kivirikko KI. Prolyl 4-hydroxylase from Volvox carteri. A low-M_r enzyme antigenically related to the alpha subunit of the vertebrate enzyme. Biochem J. 1988; 256:257–263. PMID: 2851981.

9. Wojtaszek P, Smith CG, Bolwell GP. Ultrastructural localisation and further biochemical characterisation of prolyl 4-hydroxylase from Phaseolus vulgaris: comparative analysis. Int J Biochem Cell Biol. 1999; 31:463–477. PMID: 10224670.

10. Kivirikko KI, Myllyla R, Pihlajaniemi T. Harding JJ, Crabbe JC. Hydroxylation of proline and lysine residues in collagens and other animal and plant proteins. Post-Translational Modifications of Proteins. 1992. Boca Raton, FL: CRC Press;p. 1–51.

11. Kivirikko KI, Myllyharju J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol. 1998; 16:357–368. PMID: 9524356.

12. Kivirikko KI, Pihlajaniemi T. Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4-hydroxylases. Adv Enzymol Relat Areas Mol Biol. 1998; 72:325–398. PMID: 9559057.

13. Hieta R, Myllyharju J. Cloning and characterization of a low molecular weight prolyl 4-hydroxylase from Arabidopsis thaliana. Effective hydroxylation of proline-rich, collagen-like, and hypoxia-inducible transcription factor alpha-like peptides. J Biol Chem. 2002; 277:23965–23971. PMID: 11976332.

14. Smith MC, Burns N, Sayers JR, Sorrell JA, Casjens SR, Hendrix RW. Bacteriophage collagen. Science. 1998; 279:1834. PMID: 9537896.

15. Eriksson M, Myllyharju J, Tu H, Hellman M, Kivirikko KI. Evidence for 4-hydroxyproline in viral proteins. Characterization of a viral prolyl 4-hydroxylase and its peptide substrates. J Biol Chem. 1999; 274:22131–22134. PMID: 10428773.

16. Xu Y, Keene DR, Bujnicki JM, Höök M, Lukomski S. Streptococcal Scl1 and Scl2 proteins form collagen-like triple helices. J Biol Chem. 2002; 277:27312–27318. PMID: 11976327.

17. Annunen P, Helaakoski T, Myllyharju J, Veijola J, Pihlajaniemi T, Kivirikko KI. Cloning of the human prolyl 4-hydroxylase alpha subunit isoform alpha(II) and characterization of the type II enzyme tetramer. The alpha(I) and alpha(II) subunits do not form a mixed alpha(I)alpha(II)beta2 tetramer. J Biol Chem. 1997; 272:17342–17348. PMID: 9211872.

18. Friedman L, Higgin JJ, Moulder G, Barstead R, Raines RT, Kimble J. Prolyl 4-hydroxylase is required for viability and morphogenesis in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2000; 97:4736–4741. PMID: 10781079.

19. Helaakoski T, Annunen P, Vuori K, MacNeil IA, Pihlajaniemi T, Kivirikko KI. Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an α₂β₂ tetramer with the protein disulfide-isomerase/β subunit. Proc Natl Acad Sci U S A. 1995; 92:4427–4431. PMID: 7753822.

20. Helaakoski T, Vuori K, Myllylä R, Kivirikko KI, Pihlajaniemi T. Molecular cloning of the alpha-subunit of human prolyl 4-hydroxylase: the complete cDNA-derived amino acid sequence and evidence for alternative splicing of RNA transcripts. Proc Natl Acad Sci U S A. 1989; 86:4392–4396. PMID: 2543975.

21. Annunen P, Autio-Harmainen H, Kivirikko KI. The novel type II prolyl 4-hydroxylase is the main enzyme form in chondrocytes and capillary endothelial cells, whereas the type I enzyme predominates in most cells. J Biol Chem. 1998; 273:5989–5992. PMID: 9497309.

22. Semenza GL, Koury ST, Nejfelt MK, Gearhart JD, Antonarakis SE. Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci U S A. 1991; 88:8725–8729. PMID: 1924331.

23. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92:5510–5514. PMID: 7539918.

24. Reyes H, Reisz-Porszasz S, Hankinson O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science. 1992; 256:1193–1195. PMID: 1317062.

25. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006; 70:1469–1480. PMID: 16887934.

26. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev. 1998; 8:588–594. PMID: 9794818.

27. Crews ST. Control of cell lineage-specific development and transcription by bHLH-PAS proteins. Genes Dev. 1998; 12:607–620. PMID: 9499397.

28. Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 1999; 18:1905–1914. PMID: 10202154.

29. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997; 11:72–82. PMID: 9000051.

30. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 1998; 12:3320–3324. PMID: 9808618.

31. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature. 2001; 414:550–554. PMID: 11734856.

32. Ruas JL, Poellinger L, Pereira T. Functional analysis of hypoxia-inducible factor-1 alpha-mediated transactivation. Identification of amino acid residues critical for transcriptional activation and/or interaction with CREB-binding protein. J Biol Chem. 2002; 277:38723–38730. PMID: 12133832.

33. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002; 295:858–861. PMID: 11823643.

34. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A. 2000; 97:10430–10435. PMID: 10973499.

35. Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem. 1997; 272:11205–11214. PMID: 9111021.

36. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001; 294:1337–1340. PMID: 11598268.

37. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107:43–54. PMID: 11595184.

38. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation. Science. 2001; 292:468–472. PMID: 11292861.

39. Bruick RK, McKnight SL. A conserved family of prolyl 4-hydroxylases that modify HIF. Science. 2001; 294:1337–1340. PMID: 11598268.

40. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Günzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002; 99:13459–13464. PMID: 12351678.

41. Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hütter J, Schramm M, Flamme I. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun. 2002; 296:343–349. PMID: 12163023.

42. Lieb ME, Menzies K, Moschella MC, Ni R, Taubman MB. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem Cell Biol. 2002; 80:421–426. PMID: 12234095.

43. Fraisl P, Aragonés J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov. 2009; 8:139–152. PMID: 19165233.

44. Srinivas V, Zhang LP, Zhu XH, Caro J. Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun. 1999; 260:557–561. PMID: 10403805.

45. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001; 20:5197–5206. PMID: 11566883.

46. Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci. 2003; 116:3041–3049. PMID: 12829734.

47. Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature. 2002; 417:975–978. PMID: 12050673.

48. Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science. 2002; 296:1886–1889. PMID: 12004076.

49. Ivan M, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev. 2001; 11:27–34. PMID: 11163147.

50. Takahashi Y, Takahashi S, Shiga Y, Yoshimi T, Miura T. Hypoxic induction of prolyl 4-hydroxylase alpha (I) in cultured cells. J Biol Chem. 2000; 275:14139–14146. PMID: 10799490.

51. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3:721–732. PMID: 13130303.

52. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med. 1995; 182:1683–1693. PMID: 7500013.

53. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res. 1999; 59:3915–3918. PMID: 10463582.

54. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, Semenza GL. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003; 63:1138–1143. PMID: 12615733.

55. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994; 269:23757–23763. PMID: 8089148.

56. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996; 16:4604–4613. PMID: 8756616.

57. Brahimi-Horn C, Mazure N, Pouysségur J. Signalling via the hypoxia-inducible factor-1alpha requires multiple posttranslational modifications. Cell Signal. 2005; 17:1–9. PMID: 15451019.

58. Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003; 22:4082–4090. PMID: 12912907.

59. Jaffe R, Jauniaux E, Hustin J. Maternal circulation in the first-trimester human placenta--myth or reality? Am J Obstet Gynecol. 1997; 176:695–705. PMID: 9077631.

60. Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, Post M. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest. 2000; 105:577–587. PMID: 10712429.

61. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998; 17:3005–3015. PMID: 9606183.

62. Kotch LE, Iyer NV, Laughner E, Semenza GL. Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol. 1999; 209:254–267. PMID: 10328919.

63. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev. 2001; 15:2865–2876. PMID: 11691837.

64. Yun Z, Maecker HL, Johnson RS, Giaccia AJ. Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002; 2:331–341. PMID: 11879638.

65. Tomita S, Ueno M, Sakamoto M, Kitahama Y, Ueki M, Maekawa N, Sakamoto H, Gassmann M, Kageyama R, Ueda N, Gonzalez FJ, Takahama Y. Defective brain development in mice lacking the Hif-1alpha gene in neural cells. Mol Cell Biol. 2003; 23:6739–6749. PMID: 12972594.

66. Günzler V, Brocks D, Henke S, Myllylä R, Geiger R, Kivirikko KI. Syncatalytic inactivation of prolyl 4-hydroxylase by synthetic peptides containing the unphysiologic amino acid 5-oxaproline. J Biol Chem. 1988; 263:19498–19504. PMID: 2848831.

67. Baader E, Tschank G, Baringhaus KH, Burghard H, Günzler V. Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro, in isolated microsomes and in embryonic chicken tissues. Biochem J. 1994; 300:525–530. PMID: 8002959.

68. Hanauske-Abel HM, Günzler V. A stereochemical concept for the catalytic mechanism of prolylhydroxylase: applicability to classification and design of inhibitors. J Theor Biol. 1982; 94:421–455. PMID: 6281585.

69. Majamaa K, Hanauske-Abel HM, Günzler V, Kivirikko KI. The 2-oxoglutarate binding site of prolyl 4-hydroxylase. Identification of distinct subsites and evidence for 2-oxoglutarate decarboxylation in a ligand reaction at the enzyme-bound ferrous ion. Eur J Biochem. 1984; 138:239–245. PMID: 6321169.

70. Cunliffe CJ, Franklin TJ, Hales NJ, Hill GB. Novel inhibitors of prolyl 4-hydroxylase 3 Inhibition by the substrate analogue N-oxaloglycine and its derivatives. J Med Chem. 1992; 35:2652–2658. PMID: 1321909.

71. Majamaa K, Günzler V, Hanauske-Abel HM, Myllylä R, Kivirikko KI. Partial identity of the 2-oxoglutarate and ascorbate binding sites of prolyl 4-hydroxylase. J Biol Chem. 1986; 261:7819–7823. PMID: 3011801.

72. McCaffrey TA, Pomerantz KB, Sanborn TA, Spokojny AM, Du B, Park MH, Folk JE, Lamberg A, Kivirikko KI, Falcone DJ, et al. Specific inhibition of eIF-5A and collagen hydroxylation by a single agent. Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries. J Clin Invest. 1995; 95:446–455. PMID: 7860726.

73. Günzler V, Hanauske-Abel HM, Myllylä R, Mohr J, Kivirikko KI. Time-dependent inactivation of chick-embryo prolyl 4-hydroxylase by coumalic acid. Evidence for a syncatalytic mechanism. Biochem J. 1987; 242:163–169. PMID: 3036081.

74. Günzler V, Hanauske-Abel HM, Myllylä R, Kaska DD, Hanauske A, Kivirikko KI. Syncatalytic inactivation of prolyl 4-hydroxylase by anthracyclines. Biochem J. 1988; 251:365–372. PMID: 2840891.

75. Schlemminger I, Mole DR, McNeill LA, Dhanda A, Hewitson KS, Tian YM, Ratcliffe PJ, Pugh CW, Schofield CJ. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorg Med Chem Lett. 2003; 13:1451–1454. PMID: 12668010.

76. Knowles HJ, Tian YM, Mole DR, Harris AL. Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ Res. 2004; 95:162–169. PMID: 15192023.

77. Son ED, Choi GH, Kim H, Lee B, Chang IS, Hwang JS. Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts, and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice. Biol Pharm Bull. 2007; 30:1395–1399. PMID: 17666792.

78. Wright G, Higgin JJ, Raines RT, Steenbergen C, Murphy E. Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, heme oxygenase-1, and nitric-oxide synthase proteins and confers protection from metabolic inhibition to cardiomyocytes. J Biol Chem. 2003; 278:20235–20239. PMID: 12649278.

79. Ockaili R, Natarajan R, Salloum F, Fisher BJ, Jones D, Fowler AA 3rd, Kukreja RC. 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–H548. PMID: 15805230.

80. Hölscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, Wielockx B, Breier G, Katschinski DM, Zieseniss A. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011; 286:11185–11194. PMID: 21270129.

81. Hyvärinen J, Hassinen IE, Sormunen R, Mäki JM, Kivirikko KI, Koivunen P, Myllyharju J. Hearts of hypoxia-inducible factor prolyl 4-hydroxylase-2 hypomorphic mice show protection against acute ischemia-reperfusion injury. J Biol Chem. 2010; 285:13646–13657. PMID: 20185832.

82. Zhang J, Li D. Effect of conjugated linoleic acid on inhibition of prolyl hydroxylase 1 in hearts of mice. Lipids Health Dis. 2012; 11:22. PMID: 22313584.

83. Francis GS, McDonald KM, Cohn JN. Neurohumoral activation in preclinical heart failure. Remodeling and the potential for intervention. Circulation. 1993; 87(5 Suppl):IV90–IV96. PMID: 8097970.

84. Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation. 2001; 104:2216–2221. PMID: 11684634.

85. Fielitz J, Philipp S, Herda LR, Schuch E, Pilz B, Schubert C, Günzler V, Willenbrock R, Regitz-Zagrosek V. Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding. Eur J Heart Fail. 2007; 9:336–342. PMID: 17145199.

86. Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG Jr. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008; 111:3236–3244. PMID: 18096761.

87. Hewitson KS, Schofield CJ. The HIF pathway as a therapeutic target. Drug Discov Today. 2004; 9:704–711. PMID: 15341784.

88. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003; 278:19575–19578. PMID: 12639949.

89. Bordoli MR, Stiehl DP, Borsig L, Kristiansen G, Hausladen S, Schraml P, Wenger RH, Camenisch G. Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. Oncogene. 2011; 30:548–560. PMID: 20856199.

90. Xie G, Zheng L, Ou J, Huang H, He J, Li J, Pan F, Liang H. Low expression of prolyl hydroxylase 2 is associated with tumor grade and poor prognosis in patients with colorectal cancer. Exp Biol Med (Maywood). 2012; 237:860–866. PMID: 22802519.

91. Heindryckx F, Kuchnio A, Casteleyn C, Coulon S, Olievier K, Colle I, Geerts A, Libbrecht L, Carmeliet P, Van Vlierberghe H. Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice. J Hepatol. 2012; 57:61–68. PMID: 22420978.

92. Klotzsche-von Ameln A, Muschter A, Heimesaat MM, Breier G, Wielockx B. HIF prolyl hydroxylase-2 inhibition diminishes tumor growth through matrix metalloproteinase-induced TGFβ activation. Cancer Biol Ther. 2012; 13:216–223. PMID: 22354010.

93. Asikainen TM, Waleh NS, Schneider BK, Clyman RI, White CW. Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo. Am J Physiol Lung Cell Mol Physiol. 2006; 291:L588–L595. PMID: 16679381.

94. Chen YR, Dai AG, Hu RC, Kong CC. The expression of hypoxia-inducible factor-1alpha and its hydroxylases in pulmonary arteries of patient with chronic obstructive pulmonary disease. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012; 28:234–238. PMID: 22860423.

95. Warnecke C, Griethe W, Weidemann A, Jürgensen JS, Willam C, Bachmann S, Ivashchenko Y, Wagner I, Frei U, Wiesener M, Eckardt KU. Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J. 2003; 17:1186–1188. PMID: 12709400.

96. Evans CE, Humphries J, Waltham M, Saha P, Mattock K, Patel A, Ahmad A, Wadoodi A, Modarai B, Burnand K, Smith A. Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution. Thromb Res. 2011; 128:346–351. PMID: 21621825.

97. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC, Patton SM, Connor JR, Cherny RA, Volitakis I, Bush AI, Langsetmo I, Seeley T, Gunzler V, Ratan RR. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem. 2005; 280:41732–41743. PMID: 16227210.

98. Takizawa S, Nagata E, Luo HR. Novel neuroprotective agents: a HIF activator and an Akt activator. Rinsho Shinkeigaku. 2012; 52:911–912. PMID: 23196464.

99. Niatsetskaya Z, Basso M, Speer RE, McConoughey SJ, Coppola G, Ma TC, Ratan RR. HIF prolyl hydroxylase inhibitors prevent neuronal death induced by mitochondrial toxins: therapeutic implications for Huntington's disease and Alzheimer's disease. Antioxid Redox Signal. 2010; 12:435–443. PMID: 19659431.

100. Lee DW, Rajagopalan S, Siddiq A, Gwiazda R, Yang L, Beal MF, Ratan RR, Andersen JK. Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem. 2009; 284:29065–29076. PMID: 19679656.

101. Chinta SJ, Rajagopalan S, Ganesan A, Andersen JK. A possible novel anti-inflammatory mechanism for the pharmacological prolyl hydroxylase inhibitor 3,4-dihydroxybenzoate: implications for use as a therapeutic for Parkinson's disease. Parkinsons Dis. 2012; 2012:364684. PMID: 22666629.

102. Johansen JL, Sager TN, Lotharius J, Witten L, Mørk A, Egebjerg J, Thirstrup K. HIF prolyl hydroxylase inhibition increases cell viability and potentiates dopamine release in dopaminergic cells. J Neurochem. 2010; 115:209–219. PMID: 20649842.

103. Nangaku M, Rosenberger C, Heyman SN, Eckardt KU. HIF regulation in kidney disease. Clin Exp Pharmacol Physiol. 2012; [Epub ahead of print].

104. Kapitsinou PP, Jaffe J, Michael M, Swan CE, Duffy KJ, Erickson-Miller CL, Haase VH. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol. 2012; 302:F1172–F1179. PMID: 22262480.

105. Elks PM, van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MK, Walmsley SR, Renshaw SA. Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood. 2011; 118:712–722. PMID: 21555741.

106. Walmsley SR, Chilvers ER, Thompson AA, Vaughan K, Marriott HM, Parker LC, Shaw G, Parmar S, Schneider M, Sabroe I, Dockrell DH, Milo M, Taylor CT, Johnson RS, Pugh CW, Ratcliffe PJ, Maxwell PH, Carmeliet P, Whyte MK. Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest. 2011; 121:1053–1063. PMID: 21317538.

107. Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP, Maxwell PH, Carmeliet P, Fallon PG, Schneider M, Taylor CT. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology. 2010; 139:2093–2101. PMID: 20600011.

108. Duan LJ, Takeda K, Fong GH. Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced retinopathy in neonatal mice. Am J Pathol. 2011; 178:1881–1890. PMID: 21435465.

109. Cioffi CL, Liu XQ, Kosinski PA, Garay M, Bowen BR. Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun. 2003; 303:947–953. PMID: 12670503.

110. Bernhardt WM, Câmpean V, Kany S, Jürgensen JS, Weidemann A, Warnecke C, Arend M, Klaus S, Günzler V, Amann K, Willam C, Wiesener MS, Eckardt KU. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol. 2006; 17:1970–1978. PMID: 16762988.

111. Ran R, Xu H, Lu A, Bernaudin M, Sharp FR. Hypoxia preconditioning in the brain. Dev Neurosci. 2005; 27:87–92. PMID: 16046841.

112. 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. PMID: 18273560.

113. Lushnikova I, Orlovsky M, Dosenko V, Maistrenko A, Skibo G. Brief anoxia preconditioning and HIF prolyl-hydroxylase inhibition enhances neuronal resistance in organotypic hippocampal slices on model of ischemic damage. Brain Res. 2011; 1386:175–183. PMID: 21338581.

114. Giusti S, Fiszer de Plazas S. Neuroprotection by hypoxic preconditioning involves upregulation of hypoxia-inducible factor-1 in a prenatal model of acute hypoxia. J Neurosci Res. 2012; 90:468–478. PMID: 21953610.

115. Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragonés J, Mazzone M, Mairbäurl H, De Bock K, Jeoung NH, Mollenhauer M, Georgiadou M, Bishop T, Roncal C, Sutherland A, Jordan B, Gallez B, Weitz J, Harris RA, Maxwell P, Baes M, Ratcliffe P, Carmeliet P. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology. 2010; 138:1143–1154. PMID: 19818783.

116. Muz B, Larsen H, Madden L, Kiriakidis S, Paleolog EM. Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis. Arthritis Rheum. 2012; 64:2856–2867. PMID: 22488178.