Aitbaev K A, Murkamilov I Т, Fomin V V
Scientific and Research Institute of molecular biology and medicine, Bishkek, Kyrgyzstan.
I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan.
Ter Arkh. 2018 Aug 27;90(8):86-94. doi: 10.26442/terarkh201890886-94.
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.
缺氧诱导因子脯氨酰-4-羟化酶（HIF-P4Hs）是一类酶，在常氧条件下，它们会导致HIF转录蛋白降解，而HIF转录蛋白可调节包括红细胞生成、血糖水平和脂质代谢在内的多种代谢过程。相反，在缺氧条件下，它们的活性受到抑制，HIF得以稳定。这种机制，即通过抑制HIF-P4Hs来稳定HIF，是研发用于治疗肾性贫血药物的基础，目前这些药物正处于临床试验的2期和3期，并显示出令人鼓舞的结果。最近，也有报道称抑制HIF-P4Hs对治疗心脏代谢疾病——冠心病、高血压、肥胖、代谢综合征、糖尿病心肌病和动脉粥样硬化有效。本综述基于最新数据，详细讨论了在这些病理状况下抑制HIF-P4Hs治疗作用的分子机制，并提供证据表明这些机制与HIF稳定和基因表达、改善灌注和内皮功能、将代谢从氧化磷酸化重编程为无氧糖酵解、减轻炎症以及对先天免疫系统产生有益影响有关。
