Ингибирование HIF-пролил 4-гидроксилаз как перспективный подход к терапии кардиометаболических заболеваний
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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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Prolyl-4-hydroxylases of hypoxia-inducible factor (HIF-P4Hs) are enzymes that, under the conditions of normoxia, cause degradation of the HIF-transcriptional protein, which regulates a number of metabolic processes, including erythropoiesis, glucose level and lipid metabolism. In hypoxic conditions, on the contrary, their activity is suppressed and HIF stabilization takes place. This mechanism, i.e. stabilization of HIF by inhibition of HIF-P4Hs was the basis for the development of drugs designed for treatment of renal anemia, which are currently in stages 2 and 3 of clinical trials and are showing encouraging results. Recently, it has also been reported that inhibition of HIF-P4Hs can be effective in treatment of cardiometabolic diseases – coronary heart disease, hypertension, obesity, metabolic syndrome, diabetic cardiomyopathy and atherosclerosis. The review, based on the most recent data, discusses in detail molecular mechanisms of therapeutic effect of HIF-P4Hs inhibition in these pathological conditions and provides evidence that these mechanisms are associated with HIF stabilization and gene expression, improving perfusion and endothelial function, reprogramming metabolism from oxidative phosphorylation to anaerobic glycolysis, reducing inflammation and having beneficial effect on the innate immune system.
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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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
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
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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
________________________________________________
K.A. Aitbaev 1, I.Т. Murkamilov 2,3, V. V. Fomin 4
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