Inhibition of HIF-prolyl 4-hydroxylases as a promising approach to the therapy of cardiometabolic diseases


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Abstract

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.

About the authors

K A Aitbaev

Scientific and Research Institute of molecular biology and medicine

д.м.н., проф., зав. лаб. патологической физиологии НИИ молекулярной биологии и медицины Bishkek, Kyrgyzstan

I T Murkamilov

I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan; Kyrgyz Russian Slavic University named after the First President of Russia B.N. Yeltsin

Email: murkamilov.i@mail.ru
к.м.н., нефролог, ассистент каф. факультетской терапии Кыргызской государственной медицинской академии им. И.К. Ахунбаева Bishkek, Kyrgyzstan

V V Fomin

I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)

д.м.н., член-корр. РАН, проф., зав. каф. факультетской терапии № 1, проректор по научно-исследовательской и клинической работе Первого МГМУ им. И.М. Сеченова (Сеченовский Университет) Moscow, Russia

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