HIF-Cytoprotection
Cytoprotective Effects of EPO
Under hypoxic conditions, HIF stimulates the production of erythropoietin (EPO), a hormone that functions to prevent apoptosis (programmed cell death). During erythropoiesis, EPO acts on the bone marrow to prevent progenitor cells from dying so that they may become mature red blood cells. Recent preclinical and clinical data demonstrate that EPO is also a significant cytoprotective factor that can mitigate damage and pathologies caused by hypoxic insults, such as myocardial infarction, stroke, and acute kidney injury. For example, a small clinical study conducted in patients experiencing an ischemic stroke showed that patients treated with recombinant human EPO (rHuEPO) within five hours after onset of injury had better functional outcomes and a less prominent neurological deficit.1
Other pilot studies in humans demonstrate the potential to treat chronic degenerative diseases with rHuEPO, such as multiple sclerosis2 and schizophrenia.3 Delaying the progression of chronic kidney disease has been demonstrated in several placebo controlled studies of erythropoiesis stimulating agents (ESA),4-6 which could be attributable to renoprotective effects of EPO. With respect to chronic cardioprotection, studies in pigs using rHuEPO suggest that the greatest functional benefit is derived from the apparent effects of rHuEPO on remodeling of myocardial tissue in the weeks following the initial ischemic event.7
Beyond EPO: Comprehensive Cytoprotection with HIF-PHI
HIF-mediated cytoprotection is expected to embody more than EPO effects. For example, preclinical studies have demonstrated that stabilization of HIF using HIF-PHI can mobilize a coordinated set of cytoprotective mechanisms, including expression of soluble anti-apoptotic factors (e.g., EPO and VEGF) and expression of glycolytic enzymes (e.g., phosphofructokinase-L), which may play an important role in preservation of tissue by promoting ATP generation through increased glycolysis in the setting of insufficient oxygen.8,9 The tissue-protective effects of HIF-PHI therapy have also been experimentally associated with the ability of these compounds to attenuate expression of inflammatory mediators (e.g., IL-6, MCP-1 and COX2). Inflammation is considered a key factor in tissue injury in organs subjected to ischemia, especially as part of reperfusion injury that occurs upon restoration of blood flow to the affected tissue or as associated with chronic degenerative diseases.
Other important HIF-mediated factors shown to be induced by HIF-PHI include anti-oxidant enzymes, such as heme-oxygenase-1 (HO-1), which decrease free radical damage and limit reperfusion injury and vasodilatory factors, such as nitric oxide and adrenomedullin (ADM), which enhance tissue perfusion.9,10
The pharmacological stabilization of HIF offers an attractive approach to stimulate a comprehensive, multi-factorial cytoprotective response that is expected to provide therapeutic benefit in treating organs and tissues that experience potentially life-threatening oxygen deprivation. In cases where potential for tissue injury can be predicted, such as with elective surgical procedures (e.g., coronary interventions, organ transplant), a pre-treatment approach with HIF-PHI could be used to enhance the resistance of an organ or tissue to injury and to prevent further damage from reperfusion injury. HIF-PHI therapy may also prove beneficial in treating chronic degenerative diseases with an underlying inflammatory component, such as multiple sclerosis.
FibroGen is developing HIF-PHI that can trigger significant increases in circulating endogenous EPO and upregulate other protective factors and mechanisms.
Read more about HIF-PHI therapy for:
References
- Ehrenreich et al. (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8(8):495-505.
- Ehrenreich et al. (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130(Pt 10):2577-88.
- Ehrenreich et al. (2007) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12(2):206-20.
- Gouva C et al. (2004) Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 66: (2):753-760.
- Kuriyama S et al. (1997) Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 77: (2):176-185.
- Teplan V et al. (2003) Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low-protein diet: Czech multicenter study. American Journal of Kidney Disease 41: (3 Suppl 1):S26-S30.
- Toma C et al. (2007) Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion. J Mol Cell Cardiol 43(2):130-6.
- Wang Q et al. (2006) Renoprotective and therapeutic efficacy of the HIF prolyl hydroxylase inhibitor FG-4539 in experimental ischemia-reperfusion induced acute kidney injury JASN 17:325A.
- Langsetmo I et al. (2006) Inhibition of HIF-Prolyl Hydroxylases with FG-4539 is neuroprotective in a mouse model of permanent focal ischemia. International Stroke Conference 2006 Abstract 427.
- Guo et al. (2004) Improvement of Kidney Function in a rat model of renal ischemia-reperfusion injury by treatment with a novel HIF Prolyly Hydroxylase Inhibitor. JASN 2004;15:460A.
