Inhibiting prolyl hydroxylase induces ischemic preconditioning pathways and reduces stroke brain injury

Hypoxia-inducible factors (HIF) are components of an endogenous oxygen-sensing system. HIF-1α is stimulated by hypoxia, as occurs in ischemia. A transcriptional activation of gene and protein expression provides cellular protection against many types of stress. HIF prolyl 4-hydroxylase (PHD) enzymes are responsible for HIF oxygen sensing and increased cellular protective transcription changes. Under normoxia, hydroxylation of HIF-1α by PHD results in endogenous HIF degradation and thus suppression of the HIF signaling pathway. Under hypoxia or in the presence of PHD inhibition, hydroxylation of HIF-1α by PHD cannot occur. As a result, HIF-1α is not degraded but instead dimerizes with HIF-1β, resulting in the stimulation of protective gene and protein expression. Thus, a short period of ischemia to a tissue bed (e.g., as used in ischemic preconditioning paradigms) and inhibition of PHD can both result in tissue or end-organ protection. In this paper, we discuss the regulation of oxygen sensing by PHD and the effects of PHD inhibition on cellular protection via HIF Specifically, we review PHD-inhibition-induced neuroprotection in the setting of stroke and cerebral ischemia. To date, preclinical studies have demonstrated that PHD inhibition can produce brain and neurological protection. Future human clinical stroke trials are needed to validate preclinical efficacy data.