The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Kant, Ravi (Department of Pharmaceutical Sciences and Drug Research, Punjabi University) ;
  • Bali, Anjana (Department of Pharmaceutical Sciences and Drug Research, Punjabi University) ;
  • Singh, Nirmal (Department of Pharmaceutical Sciences and Drug Research, Punjabi University) ;
  • Jaggi, Amteshwar Singh (Department of Pharmaceutical Sciences and Drug Research, Punjabi University)
  • Received : 2013.02.04
  • Accepted : 2013.03.06
  • Published : 2013.04.30
Download PDF
⟨ Previous Next ⟩

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.

Keywords

References

  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 hypoxiainducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat. J Cardiovasc Pharmacol. 2010;56:147-155. https://doi.org/10.1097/FJC.0b013e3181e2bfef
  2. Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med. 2001;33:7-21. https://doi.org/10.3109/07853890109002055
  3. Johnstone IL. Cuticle collagen genes. Expression in Caenorhabditis elegans. Trends Genet. 2000;16:21-27.
  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. https://doi.org/10.1074/jbc.M203824200
  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. https://doi.org/10.1074/jbc.274.10.6790
  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. https://doi.org/10.1016/S0166-6851(01)00317-6
  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. https://doi.org/10.1074/jbc.M210381200
  8. Kaska DD, Myllyla R, Gunzler V, Gibor A, Kivirikko KI. Prolyl 4-hydroxylase from Volvox carteri. A low-Mr enzyme antigenically related to the alpha subunit of the vertebrate enzyme. Biochem J. 1988;256:257-263. https://doi.org/10.1042/bj2560257
  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. https://doi.org/10.1016/S1357-2725(98)00126-5
  10. Kivirikko, KI, Myllyla R, Pihlajaniemi T. Hydroxylation of proline and lysine residues in collagens and other animal and plant proteins. In: Harding JJ, Crabbe JC, eds. Post-Translational Modifications of Proteins. Boca Raton, FL: CRC Press; 1992. p.1-51.
  11. Kivirikko KI, Myllyharju J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol. 1998;16: 357-368. https://doi.org/10.1016/S0945-053X(98)90009-9
  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.
  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. https://doi.org/10.1074/jbc.M201865200
  14. Smith MC, Burns N, Sayers JR, Sorrell JA, Casjens SR, Hendrix RW. Bacteriophage collagen. Science. 1998;279:1834. https://doi.org/10.1126/science.279.5348.183d
  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. https://doi.org/10.1074/jbc.274.32.22131
  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. https://doi.org/10.1074/jbc.M201163200
  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. https://doi.org/10.1074/jbc.272.28.17342
  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. https://doi.org/10.1073/pnas.97.9.4736
  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 ${\alpha}_2{\beta}_2$ tetramer with the protein disulfide-isomerase/$\beta$ subunit. Proc Natl Acad Sci U S A. 1995; 92:4427-4431. https://doi.org/10.1073/pnas.92.10.4427
  20. Helaakoski T, Vuori K, Myllyla 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. https://doi.org/10.1073/pnas.86.12.4392
  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. https://doi.org/10.1074/jbc.273.11.5989
  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. https://doi.org/10.1073/pnas.88.19.8725
  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. https://doi.org/10.1073/pnas.92.12.5510
  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. https://doi.org/10.1126/science.256.5060.1193
  25. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70:1469-1480. https://doi.org/10.1124/mol.106.027029
  26. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev. 1998;8:588-594. https://doi.org/10.1016/S0959-437X(98)80016-6
  27. Crews ST. Control of cell lineage-specific development and transcription by bHLH-PAS proteins. Genes Dev. 1998;12:607-620. https://doi.org/10.1101/gad.12.5.607
  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;18:1905-1904. https://doi.org/10.1093/emboj/18.7.1905
  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. https://doi.org/10.1101/gad.11.1.72
  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. https://doi.org/10.1101/gad.12.21.3320
  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. https://doi.org/10.1038/35107085
  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. https://doi.org/10.1074/jbc.M205051200
  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. https://doi.org/10.1126/science.1068592
  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. https://doi.org/10.1073/pnas.190332597
  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. https://doi.org/10.1074/jbc.272.17.11205
  36. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337-1340. https://doi.org/10.1126/science.1066373
  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. https://doi.org/10.1016/S0092-8674(01)00507-4
  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 $O_{2}$ -regulated prolyl hydroxylation. Science. 2001;292:468-472. https://doi.org/10.1126/science.1059796
  39. Bruick RK, McKnight SL. A conserved family of prolyl 4- hydroxylases that modify HIF. Science. 2001;294:1337-1340. https://doi.org/10.1126/science.1066373
  40. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler 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. https://doi.org/10.1073/pnas.192342099
  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. https://doi.org/10.1016/S0006-291X(02)00862-8
  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. https://doi.org/10.1139/o02-115
  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. https://doi.org/10.1038/nrd2761
  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. https://doi.org/10.1006/bbrc.1999.0878
  45. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxiainducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001;20:5197-5206. https://doi.org/10.1093/emboj/20.18.5197
  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. https://doi.org/10.1242/jcs.00655
  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. https://doi.org/10.1038/nature00767
  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. https://doi.org/10.1126/science.1073440
  49. Ivan M, Kaelin WG Jr. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev. 2001;11:27-34. https://doi.org/10.1016/S0959-437X(00)00152-0
  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. https://doi.org/10.1074/jbc.275.19.14139
  51. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721-732. https://doi.org/10.1038/nrc1187
  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. https://doi.org/10.1084/jem.182.6.1683
  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.
  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 hypoxiainducible factor 1. Cancer Res. 2003;63:1138-1143.
  55. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxiainducible factor 1. J Biol Chem. 1994;269:23757-23763.
  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. https://doi.org/10.1128/MCB.16.9.4604
  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 https://doi.org/10.1016/j.cellsig.2004.04.010
  58. 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;22:4082-4090. https://doi.org/10.1093/emboj/cdg392
  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. https://doi.org/10.1016/S0002-9378(97)70572-6
  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. https://doi.org/10.1172/JCI8316
  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. https://doi.org/10.1093/emboj/17.11.3005
  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. https://doi.org/10.1006/dbio.1999.9253
  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.
  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. https://doi.org/10.1016/S1534-5807(02)00131-4
  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. https://doi.org/10.1128/MCB.23.19.6739-6749.2003
  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.
  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. https://doi.org/10.1042/bj3000525
  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. https://doi.org/10.1016/0022-5193(82)90320-4
  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. https://doi.org/10.1111/j.1432-1033.1984.tb07907.x
  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. https://doi.org/10.1021/jm00092a016
  71. Majamaa K, Günzler V, Hanauske-Abel HM, Myllyla R, Kivirikko KI. Partial identity of the 2-oxoglutarate and ascorbate binding sites of prolyl 4-hydroxylase. J Biol Chem. 1986;261: 7819-7823.
  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. https://doi.org/10.1172/JCI117684
  73. Gunzler V, Hanauske-Abel HM, Myllyla 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. https://doi.org/10.1042/bj2420163
  74. Gunzler V, Hanauske-Abel HM, Myllyla R, Kaska DD, Hanauske A, Kivirikko KI. Syncatalytic inactivation of prolyl 4- hydroxylase by anthracyclines. Biochem J. 1988;251:365-372. https://doi.org/10.1042/bj2510365
  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. https://doi.org/10.1016/S0960-894X(03)00149-5
  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. https://doi.org/10.1161/01.RES.0000134924.89412.70
  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. https://doi.org/10.1248/bpb.30.1395
  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. https://doi.org/10.1074/jbc.M301391200
  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:H542-548. https://doi.org/10.1152/ajpheart.00089.2005
  80. Holscher 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. https://doi.org/10.1074/jbc.M110.186809
  81. Hyvarinen J, Hassinen IE, Sormunen R, Maki 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. https://doi.org/10.1074/jbc.M109.084855
  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. https://doi.org/10.1186/1476-511X-11-22
  83. Francis GS, McDonald KM, Cohn JN. Neurohumoral activation in preclinical heart failure. Remodeling and the potential for intervention. Circulation. 1993;87(5 Suppl):IV90-96.
  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. https://doi.org/10.1161/hc4301.097193
  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. https://doi.org/10.1016/j.ejheart.2006.10.006
  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. https://doi.org/10.1182/blood-2007-10-117812
  87. Hewitson KS, Schofield CJ. The HIF pathway as a therapeutic target. Drug Discov Today. 2004;9:704-711. https://doi.org/10.1016/S1359-6446(04)03202-7
  88. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003;278:19575-19578. https://doi.org/10.1074/jbc.R200030200
  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. https://doi.org/10.1038/onc.2010.433
  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. https://doi.org/10.1258/ebm.2012.011331
  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. https://doi.org/10.1016/j.jhep.2012.02.021
  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 TGF$\beta$ activation. Cancer Biol Ther. 2012;13:216-223. https://doi.org/10.4161/cbt.13.4.18830
  93. Asikainen TM, Waleh NS, Schneider BK, Clyman RI, White CW. Enhancement of angiogenic effectors through hypoxiainducible factor in preterm primate lung in vivo. Am J Physiol Lung Cell Mol Physiol. 2006;291:L588-595. https://doi.org/10.1152/ajplung.00098.2006
  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.
  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 factorpathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J. 2003;17:1186-1188. https://doi.org/10.1096/fj.02-1062fje
  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. https://doi.org/10.1016/j.thromres.2011.05.006
  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. https://doi.org/10.1074/jbc.M504963200
  98. Takizawa S, Nagata E, Luo HR. Novel neuroprotective agents: a HIF activator and an Akt activator. Rinsho Shinkeigaku. 2012;52:911-912. https://doi.org/10.5692/clinicalneurol.52.911
  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. https://doi.org/10.1089/ars.2009.2800
  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. https://doi.org/10.1074/jbc.M109.000638
  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.
  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. https://doi.org/10.1111/j.1471-4159.2010.06917.x
  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:F1172-1179. https://doi.org/10.1152/ajprenal.00667.2011
  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-1$\alpha$ (Hif-1$\alpha$ ) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood. 2011;118:712-722. https://doi.org/10.1182/blood-2010-12-324186
  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. https://doi.org/10.1172/JCI43273
  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. https://doi.org/10.1053/j.gastro.2010.06.068
  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. https://doi.org/10.1016/j.ajpath.2010.12.016
  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. https://doi.org/10.1016/S0006-291X(03)00453-4
  110. Bernhardt WM, Campean V, Kany S, Jurgensen JS, Weidemann A, Warnecke C, Arend M, Klaus S, Gunzler 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. https://doi.org/10.1681/ASN.2005121302
  111. Ran R, Xu H, Lu A, Bernaudin M, Sharp FR. Hypoxia preconditioning in the brain. Dev Neurosci. 2005;27:87-92. https://doi.org/10.1159/000085979
  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. https://doi.org/10.1007/s11010-008-9717-5
  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. https://doi.org/10.1016/j.brainres.2011.02.033
  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. https://doi.org/10.1002/jnr.22766
  115. Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragones J, Mazzone M, Mairbaurl 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. https://doi.org/10.1053/j.gastro.2009.09.057
  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. https://doi.org/10.1002/art.34479

Cited by

  1. Prolyl hydroxylase inhibitors act as agents to enhance the efficiency of cell therapy vol.15, pp.12, 2015, https://doi.org/10.1517/14712598.2015.1084281
  2. Bacillus anthracis Prolyl 4-Hydroxylase Interacts with and Modifies Elongation Factor Tu vol.56, pp.43, 2013, https://doi.org/10.1021/acs.biochem.7b00601
  3. Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors vol.50, pp.1, 2013, https://doi.org/10.1080/07853890.2017.1383629