The hypoxia-inducible factors (HIFs) regulate oxygen homeostasis
6 under control of the prolyl hydroxylases (PHDs) and are considered the master transcriptional regulators that induce the expression of VEGF and other genes that regulate vascular biology, metabolism, angiogenesis, proliferation, and survival.
6 –9 The PHDs belong to the superfamily of 2-oxoglutatate (OG)-dependent dioxygenases that catalyze hydroxylation in the conserved prolines of the oxygen-dependent degradation domain (ODDD), which requires O
2 and 2-OG as cosubstrates and Fe
2 as a cofactor.
10 PHDs serve as oxygen sensors that regulate the stability or degradation of the HIFs in an oxygen-dependent manner. In normoxia or hyperoxia, PHDs hydroxylize the prolines of HIFs, which are captured by Von Hipple Lindau protein (pVHL) ubiquitin E3 ligase complex and degraded by the proteasome. By contrast, in hypoxia, PHDs do not initiate this reaction because of the shortage of O
2 and, therefore, HIF is stabilized.
11,12 To date, three PHD isoforms (PHD1, 2, and 3) have been discovered and they appear to play overlying, but not redundant roles that sometimes differ in different organ systems. For instance, PHD2 is necessary for normal embryonic development and its homozygous deletion is lethal, while PHD1 protects cells or tissues from oxidative damage in hypoxic conditions.
7 PHD1-deficient muscle cells protect themselves against oxidative damage in hypoxic conditions by switching from aerobic to anaerobic metabolism and by slowing mitochondrial respiration,
13 making inhibition of PHD1 a very promising strategy for preventing ischemic retinopathies. PHD1 inhibition also protects the liver from ischemia and/or reperfusion injury
14 and it promotes survival in mesenchymal stem cells
15 and intestinal epithelial cells.
16 In some systems, inhibition of PHDs promotes angiogenesis, but in other scenarios, it provides neuroprotection without angiogenesis.
17,18 In the oxygen-induced retinopathy (OIR) model of ROP, nondiscriminative pharmacological inhibition of all PHDs and other oxygen sensors prevents the hyperoxia-induced retinal vessel loss and the subsequent retinal NV that occurs in the hypoxic phase.
19 However, the precise role of the distinct PHD isoforms in the regulation of oxygen homeostasis and the stability of the HIF isoforms is poorly understood.