Ингибирование HIF-пролил 4-гидроксилаз как перспективный подход к терапии кардиометаболических заболеваний
Ингибирование HIF-пролил 4-гидроксилаз как перспективный подход к терапии кардиометаболических заболеваний
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Аннотация
Пролил-4-гидроксилазы индуцируемого гипоксией фактора (HIF-P4Hs) представляют собой ферменты, которые, в условиях нормоксии, вызывают деградацию HIF – транскрипционного белка, регулирующего многие метаболические процессы, в том числе эритропоэз, уровень глюкозы и липидный обмен. В условиях гипоксии, напротив, их активность подавляется и происходит стабилизация HIF. Данный механизм, т. е. стабилизация HIF путем ингибирования HIF-P4Hs, положен в основу разработки препаратов для лечения почечной анемии, которые в настоящее время находятся во 2-й и 3-й фазах клинических испытаний и показывают обнадеживающие результаты. Недавно получены данные о том, что ингибирование HIF-P4Hs может быть эффективным и при лечении кардиометаболических заболеваний – ишемической болезни сердца, гипертензии, ожирения, метаболического синдрома, диабетической кардиомиопатии и атеросклероза. В обзоре на основе самых последних данных подробно обсуждаются молекулярные механизмы терапевтического действия ингибирования HIF-P4Hs при указанных патологических состояниях и приводятся доказательства того, что эти механизмы связаны с HIF-стабилизацией и экспрессией генов, которые улучшают перфузию и эндотелиальную функцию, перепрограммируют метаболизм с окислительного фосфорилирования на анаэробный гликолиз, уменьшают воспаление и благотворно влияют на врожденную иммунную систему.
Ключевые слова: гипоксия, индуцируемый гипоксией фактор (HIF), HIF-пролил-4-гидроксилазы (HIF-P4Hs), кардиометаболические заболевания, ишемическая болезнь сердца, ожирение, метаболический синдром, атеросклероз.
Keywords: hypoxia, hypoxia-inducible factor (HIF), HIF-prolyl-4-hydroxylases (HIF-P4Hs), cardiometabolic diseases, ischemic heart disease, obesity, metabolic syndrome, atherosclerosis.
Ключевые слова: гипоксия, индуцируемый гипоксией фактор (HIF), HIF-пролил-4-гидроксилазы (HIF-P4Hs), кардиометаболические заболевания, ишемическая болезнь сердца, ожирение, метаболический синдром, атеросклероз.
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Keywords: hypoxia, hypoxia-inducible factor (HIF), HIF-prolyl-4-hydroxylases (HIF-P4Hs), cardiometabolic diseases, ischemic heart disease, obesity, metabolic syndrome, atherosclerosis.
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3. [Aytbaev KA, Meymanaliev TS. Prevalence of atherogenic dyslipoproteinemia among highlanders. Kardiologiya. 1992;(1):9-11 (In Russ.)].
4. [Aytbaev KA, Madaminov YaK, Meymanaliev TS, et al. Study of the impact of migration in mountain regions on the blood lipoprotein system. Kosmicheskaya Biologiya i Aviakosmicheskaya Meditsina. 1990;(6):45-46 (In Russ.)].
5. [Mirrakhimov MM, Aytbaev KA, Murataliev TM. On the possibility of correcting hypercholesterolemia with high-altitude training. Kardiologiya. 2001;(7):9-11 (In Russ.)].
6. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447-5454. PMCID: PMC360482
7. Eckle T, Kohler D, Lehmann R, et al. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation. 2008;118:166-175. doi: 10.1161/CIRCULATIONAHA.107.758516
8. Ikeda J, Ichiki T, Matsuura H, et al. Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling. J Am Heart Assoc. 2013;2:e000178.
9. Rahtu-Korpela L, Karsikas S, Hörkkö S, et al. HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. Diabetes. 2014;63(10):3324-3333. doi: 10.2337/db14-0472
10. Rahtu-Korpela L, Määttä J, Dimova EY, et al. Hypoxia-inducible factor prolyl 4-hydroxylase-2 inhibition protects against development of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36:608-617.
11. Kaelin Jr WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393-402.
doi: 10.1016/j.molcel.2008.04.009
12. Myllyharju J, Koivunen P. Hypoxia-inducible factorprolyl4-hydroxylases: common and specific roles. Biol Chem. 2013;394:435-448.
doi: 10.1515/hsz-2012-0328
13. Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97-106. doi: 10.1152/physiol.00045.2008
14. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337-1340. doi: 10.1126/science.1066373
15. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family ofdioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43-54. doi: 10.1016/ S0092-8674(01)00507-4
16. Ivan M, Haberberger T, Gervasi DC, et al. 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. doi: 10.1073/pnas.192342099
17. Berra E, Benizri E, Ginouves A, et al. 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. doi: 10.1093/emboj/cdg392
18. Loenarz C, Coleman ML, Boleininger A, et al. The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplaxadhaerens. EMBO Rep. 2011;12:63-70. doi: 10. 1038/embor.2010.170
19. Appelhoff RJ, Tian YM, Raval RR, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458-38465. doi: 10. 1074/jbc.M406026200
20. Cervera AM, Apostolova N, Luna-Crespo F, et al. An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer Lett. 2006;233:131-138. doi: 10.1016/j.canlet.2005.03.004
21. Takeda K, Ho V, Takeda H, et al. Placental but not heart defect is associated with elevated HIFα levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol. 2006;26:8336-8346. doi: 10.1128/ MCB.00425-06
22. Bishop T, Gallagher D, Pascual A, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol. 2008;28:3386-3400. doi: 10.1128/MCB.02041-07
23. Lee FS, Percy MJ. The HIF pathway and erythrocytosis. Annu Rev Pathol. 2011;6:165-192. doi: 10.1146/annurev-pathol-011110-130321
24. Lorenzo FR, Huff C, Myllymäki M, et al. A genetic mechanism for
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25. McDonough MA, Loenarz C, Chowdhury R, et al. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol. 2010;20:659-672. doi: 10.1016/j.sbi.2010.08.006
26. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20:33-43. doi: 10.1016/j.tig.2003.11.004
27. Koivunen P, Hirsilä M, Remes AM, et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 2007;282:4524-4532. doi: 10.1074/jbc.M610415200
28. Hirsilä M, Koivunen P, Xu L, et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 2005;19:1308-1310. doi: 10.1096/fj.04-3399fje
29. Asikainen TM, Ahmad A, Schneider BK, et al. Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 2005;38(8):1002-1013. doi: 10.1016/j.freeradbiomed.2004.12.004
30. Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing.
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33. 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(1):68-77. doi: 10.1016/j.yjmcc.2006.04.009
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35. Hyvärinen J, Hassinen IE, Sormunen R, et al. Hearts of hypoxia-inducible factor prolyl4-hydroxylase-2 hypomorphicmice show protection against acute ischemia-reperfusion injury. J Biol Chem. 2010;285(18):13646-13657. doi: 10.1074/jbc.M109.084855
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37. Hölscher M, Silter M, Krull S, et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011;286:11185-11194. doi: 10.1074/ jbc.M110.186809
38. Adluri RS, Thirunavukkarasu M, Dunna NR, et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1alpha transcription factor and its target genes in mice. Antioxid Redox Signal. 2011;15(7):1789-1797. doi: 10.1089/ars.2010.3769
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20. Cervera AM, Apostolova N, Luna-Crespo F, et al. An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer Lett. 2006;233:131-138. doi: 10.1016/j.canlet.2005.03.004
21. Takeda K, Ho V, Takeda H, et al. Placental but not heart defect is associated with elevated HIFα levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol. 2006;26:8336-8346. doi: 10.1128/ MCB.00425-06
22. Bishop T, Gallagher D, Pascual A, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol. 2008;28:3386-3400. doi: 10.1128/MCB.02041-07
23. Lee FS, Percy MJ. The HIF pathway and erythrocytosis. Annu Rev Pathol. 2011;6:165-192. doi: 10.1146/annurev-pathol-011110-130321
24. Lorenzo FR, Huff C, Myllymäki M, et al. A genetic mechanism for
Tibetan high-altitude adaptation. Nat Genet. 2014;46:951-956.
doi: 10.1038/ng.3067
25. McDonough MA, Loenarz C, Chowdhury R, et al. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol. 2010;20:659-672. doi: 10.1016/j.sbi.2010.08.006
26. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20:33-43. doi: 10.1016/j.tig.2003.11.004
27. Koivunen P, Hirsilä M, Remes AM, et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem. 2007;282:4524-4532. doi: 10.1074/jbc.M610415200
28. Hirsilä M, Koivunen P, Xu L, et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 2005;19:1308-1310. doi: 10.1096/fj.04-3399fje
29. Asikainen TM, Ahmad A, Schneider BK, et al. Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 2005;38(8):1002-1013. doi: 10.1016/j.freeradbiomed.2004.12.004
30. Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing.
J Biol Chem. 2000;275(33):25130-25138. doi: 10.1074/jbc.M00 1914200
31. Metzen E, Zhou J, Jelkmann W, et al. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell. 2003;14(8):3470-3481. doi: 10.1091/mbc.E02-12-0791
32. Hirsilä M, Koivunen P, Gunzler V, et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003;278(33):30772-30780. doi: 10.1074/jbc.M304982200
33. 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(1):68-77. doi: 10.1016/j.yjmcc.2006.04.009
34. Huang M, Chan DA, Jia F, et al. Short hairpin RNA interference therapy for ischemic heart disease. Circulation. 2008;118(4):S226-S233. doi: 10.1161/CIRCULATIONAHA.107.760785
35. Hyvärinen J, Hassinen IE, Sormunen R, et al. Hearts of hypoxia-inducible factor prolyl4-hydroxylase-2 hypomorphicmice show protection against acute ischemia-reperfusion injury. J Biol Chem. 2010;285(18):13646-13657. doi: 10.1074/jbc.M109.084855
36. Kerkelä R, Karsikas S, Szabo Z, et al. Activation ofhypoxia response in endothelial cells contributes to ischemic cardioprotection. Mol Cell Biol. 2013;33(16):3321-3329. doi: 10.1128/MCB.00432-13
37. Hölscher M, Silter M, Krull S, et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011;286:11185-11194. doi: 10.1074/ jbc.M110.186809
38. Adluri RS, Thirunavukkarasu M, Dunna NR, et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1alpha transcription factor and its target genes in mice. Antioxid Redox Signal. 2011;15(7):1789-1797. doi: 10.1089/ars.2010.3769
39. Oriowo B, Thirunavukkarasu M, Selvaraju V, et al. Targeted gene deletion of prolyl hydroxylase domain protein 3 triggers angiogenesis and preserves cardiac function by stabilizing hypoxia inducible factor 1 alpha following myocardial infarction. Curr Pharm Des. 2014;20:1305-1310. doi: 10.2174/13816128113199990549
40. Zieseniss A, Hesse AR, Jatho A, et al. Cardiomyocyte-specific transgenic expression of prolyl-4-hydroxylase domain 3 impairs the myocardial response to ischemia. Cell Physiol Biochem. 2015;36:843-851. doi: 10.1159/000430260
41. 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(2):170-180. doi: 10.1038/ng. 2007.62
42. Karsikas S, Myllymäki M, Heikkilä M, et al. HIF-P4H-2 deficiency protects against skeletal muscle ischemia-reperfusion injury. J Mol Med (Berl). 2016;94:301-310.
43. Ong SG, Lee WH, Theodorou L, et al. HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore. Cardiovasc Res. 2014;104(1):24-36. doi: 10.1093/ cvr/cvu172
44. 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(11):3790-3803. doi: 10.1128/MCB.01580-07
45. Minamishim YA, Moslehi J, Padera RF, et al. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29(21):5729-5741. doi: 10.1128/ MCB.00331-09
46. Krishnan J, Suter M, Windak R, et al. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 2009;9(6):512-524. doi: 10.1016/j.cmet.2009.05.005
47. 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(7):774-781. doi: 10.1161/CIRCULATIONAHA.107.701516
48. Takeda Y, Costa S, Delamarre E, et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature. 2011;479(7371):122-126. doi: 10.1038/nature10507
49. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-1136. PMID:3769170
50. Gho BC, Schoemaker RG, van den Doel MA, et al. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94:2193-2200. PMID:8901671
51. Cai Z, Luo W, Zhan H, Semenza GL. Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci U S A. 2013;110:17462-17467. doi: 10.1073/pnas.1317158110
52. Davidson SM, Selvaraj P, He D, et al. Remote ischaemic preconditioning involves signalling through the SDF-1alpha/CXCR4 signalling axis. Basic Res Cardiol. 2013;108(50):377. doi: 10.1007/s00395-013-0377-6
53. Olenchock BA, Moslehi J, Baik AH, et al. EGLN1 inhibition and rerouting of alpha-ketoglutarate suffice for remote ischemic protection. Cell. 2016;164(5):884-895. doi: 10.1016/j.cell.2016.02.006
54. Martin-Puig S, Tello D, Aragones J. Novel perspectives on the PHD-HIF oxygen sensing pathway in cardioprotection mediated by IPC and RIPC. Front Physiol. 2015;6:137. doi: 10.3389/fphys.2015.00137
55. Zeng H, Chen JX. Conditional knockout of prolyl hydroxylase domain protein 2 attenuates high fat-diet-induced cardiac dysfunction in mice. PLoS One. 2014;9:e115974. doi: 10.1371/journal.pone.0115974
56. Xia Y, Gong L, Liu H, et al. Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy. Mol Cell Endocrinol. 2015;403:21-29. doi: 10.1016/j.mce.2015.01.014
57. Minamishima YA, Moslehi J, Bardeesy N, et al. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;11:3236-3244.
58. Moslehi J, Minamishima YA, Shi J, et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytesphenocopies ischemic cardiomyopathy. Circulation. 2010;122(10):1004-1016.
doi: 10.1161/CIRCULATIONAHA.109.922427
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Авторы
К.А. Айтбаев 1, И.Т. Муркамилов 2,3, В.В. Фомин 4
1 Научно-исследовательский институт молекулярной биологии и медицины при Национальном центре кардиологии и терапии Минздрава Кыргызской Республики, Бишкек, Кыргызстан;
2 Кыргызская государственная медицинская академия им. И.К. Ахунбаева, Бишкек, Кыргызстан;
3 Кыргызско-Российский Славянский университет имени первого Президента России Б.Н. Ельцина, Бишкек, Кыргызстан;
4 ФГБОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
1 Scientific and Research Institute of molecular biology and medicine, Bishkek, Kyrgyzstan;
2 I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan;
3 Kyrgyz Russian Slavic University named after the First President of Russia B.N. Yeltsin, Bishkek, Kyrgyzstan;;
4 I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia
1 Научно-исследовательский институт молекулярной биологии и медицины при Национальном центре кардиологии и терапии Минздрава Кыргызской Республики, Бишкек, Кыргызстан;
2 Кыргызская государственная медицинская академия им. И.К. Ахунбаева, Бишкек, Кыргызстан;
3 Кыргызско-Российский Славянский университет имени первого Президента России Б.Н. Ельцина, Бишкек, Кыргызстан;
4 ФГБОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
________________________________________________
1 Scientific and Research Institute of molecular biology and medicine, Bishkek, Kyrgyzstan;
2 I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan;
3 Kyrgyz Russian Slavic University named after the First President of Russia B.N. Yeltsin, Bishkek, Kyrgyzstan;;
4 I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia
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