Abstract
Hypoxia inducible factor 1 (HIF-1) plays a pivotal role in cellular responses to hypoxia. Prolyl hydroxylase 3 (PHD3) degrades HIF-1α under normoxic conditions through the hydroxylation of HIF-1α for proteolysis. Inhibiting PHD3 activity is crucial for up-regulating HIF-1α, thereby acting as a potential target for treating hypoxia-related diseases. In this study, two proline analogues (PA1 and PA2) were screened as PHD3 inhibitors with apparent EC50 values of 1.53 and 3.17 µM respectively, indicating good inhibition potency. Nine proteins, significantly regulated by PA1, were identified using 2-DE coupled with MALDI-TOF/TOF MS. Pyruvate kinase isozymes M1/M2 (PKM) and alpha-enolase 1 (ENO1), which are key modulators of glycolysis, are directly regulated by HIF-1α. Moreover, VEGF, a signal protein stimulating angiogenesis, was strongly promoted by PA1. Our findings suggest that PA1 stabilized HIF-1α as well as up-regulated glycolysis and angiogenesis proteins. Herein, for the first time, we systematically studied proline analogue PA1 as a PHD3 inhibitor, which provides innovative evidence for the treatment of HIF-related diseases.
Highlights
Oxygen homeostasis, an important organizing principle for the development and physiology of living organisms, can be disrupted by cardiovascular, pulmonary, hematological diseases and cancers [1,2]
Hypoxia inducible factor 1 (HIF-1), which functions as a master regulator of oxygen homeostasis [3,4], is a heterodimer consisting of an alpha subunit (HIF-1a) and a beta subunit (HIF1b)
Cellular HIF-1a is regulated by hydroxylation with prolyl hydroxylase 3 (PHD3), ubiquitination, and proteasomal degradation
Summary
An important organizing principle for the development and physiology of living organisms, can be disrupted by cardiovascular, pulmonary, hematological diseases and cancers [1,2]. Most iron chelators are 2-oxoglutarate (2OG) analogues which share similar simple 2OG scaffolds to chelate iron in a bidentate fashion [20] Some classical chelators, such as N-oxalylglycine (NOG) [26], dimethyloxalylglycine (DMOG) [27], ethyl-3, 4-dihydroxybenzoate (3, 4-DHB) [12], and deferoxamine mesylate (DFO) [12], can competitively inhibit the activity of PHD and stabilize HIF-1a to repair chronic disease anemia and neuronal injury. Iron chelators cannot exclusively bind to PHDs and may disturb other iron-containing proteins that maintain normal physiology and biochemistry [28] Still, these reports raise new questions as to the selectivity of HIF hydroxylase inhibitors and the extent to which their biological activity is mediated solely by inhibition of PHDs and FIH.
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