Anemia of chronic disease (ACD) is the most frequent clinical issue in patients with chronic disease. ACD is usually secondary to chronic kidney disease (CKD), cancer, and chronic infection, which is associated with poor health outcomes, increased morbidity and mortality, and substantial economic costs. Current treatment options for ACD are very limited. The discovery of the hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) pathway made it possible to develop novel therapeutic agents (such as hypoxia-inducible factor-prolyl hydroxylase inhibitor, HIF-PHI) to treat ACD by stabilizing HIF and subsequently promoting endogenous erythropoietin (EPO) production and iron absorption and utilization. Thus, HIF-PHIs appear to open a new door for the treatment of ACD patients with a novel mechanism. Here, we comprehensively reviewed the latest advancements in the application of HIF-PHIs in ACD. Specifically, we highlighted the key features of HIF-PHIs on ACD, such as stimulation of endogenous EPO, handling iron metabolism, inflammation-independent, and prolonging lifespan of red blood cells. In conclusion, the success of HIF-PHIs in the treatment of ACD may expand the therapeutic opportunity for other types of anemia beyond renal anemia.
Humans ; Anemia/metabolism* ; Chronic Disease ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism* ; Erythropoietin/metabolism* ; Prolyl-Hydroxylase Inhibitors/therapeutic use* ; Animals ; Renal Insufficiency, Chronic

OBJECTIVETo detect the expression of the plateau adaptablity gene(EPAS1, EGLN1 and PPARα) and proteins(HIF-2, PHD2 and PPARα) in rats blood, heart, liver, lung and kidney tissue after the rats exposed to high altitude.

METHODSThe Wistar rats were randomly divided into plain group(Shanghai, 55 m), acute exposure to high altitude 3400 m group, acute exposure to high altitude 4300 m group. Blood and organs of rats were collected in 1, 3, 5 days after arrival. Real time PCR and ELISA were used to compare the expression of plateau adaptablity gene and related protein between plain group and high altitude exposure groups.

RESULTSThe count of red blood cells, hemoglobin and HCT in high altitude 4300 m were higher than those in plain group. Compared with plain group, the expression of EPAS1 gene in blood, heart, liver and kidney tissue of rats at high altitude increased obviously(all P<0.05); the expression of EGLN1 in the heart, liver, brain and kidney increased, and PPARα gene in the heart, liver and kidney increased(all P<0.05). Compared with plain group, the expression of HIF-2 protein increased significantly at high altitudes in the liver, brain and kidney tissues. PHD2 and PPARα increased in the heart, liver and kidney.

CONCLUSIONPlateau adaptive genes(EPAS1, EGLN1 and PPARα) and protein(HIF-2, PHD2 and PPARα) differed in different altitude and different organizations. They might be used as target markers of plateau hypoxia.

Adaptation, Physiological ; Altitude ; Animals ; Basic Helix-Loop-Helix Transcription Factors ; metabolism ; Brain ; China ; Heart ; Hypoxia ; Hypoxia-Inducible Factor-Proline Dioxygenases ; metabolism ; Kidney ; Liver ; Lung ; PPAR alpha ; metabolism ; Procollagen-Proline Dioxygenase ; metabolism ; Rats ; Rats, Wistar

Prolyl-4-hydroxylase domain (PHDs) family is one of the most important regulatory factors in hypoxic stress. PHD2 plays a critical role in cells and tissues adaptation to the low oxygen environment. Its hydroxylation activity regulates the stability and transcriptional activity of the hypoxia-inducible factor 1 (HIF-1), which is the key factor in response to hypoxic stress. Subsequently, PHD2 acts as an important factor in oxygen homeostasis. Studies have shown that PHD2, through its regulation on HIF-1, plays an important role in the post-ischemic neovascularization. Furthermore, under hypoxic condition, PHD2 also regulates other pathways that positively regulate angiogenesis factors HIF-1 independently. Moreover, recently, several evidences have also shown that PHD2 also affects tumor growth and metastasis in a tumor microenvironment. Based on these facts, PHD2 have been considered as a potential therapeutic target both in treating ischemic diseases and tumors. Here, we review the molecular regulation mechanism of PHD2 and its physiological and pathological functions. We focus on the role of PHD2 in both therapeutic angiogenesis for ischemic disease and tumor angiogenesis, and the current progress in utilizing PHD2 as a therapeutic target.
Animals ; Humans ; Hydroxylation ; Hypoxia-Inducible Factor 1 ; metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; antagonists & inhibitors ; physiology ; Neoplasms ; blood supply ; metabolism ; pathology ; therapy ; Neovascularization, Pathologic ; metabolism ; pathology ; Tumor Microenvironment ; Vascular Diseases ; pathology ; therapy

Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases ; metabolism ; Ki-67 Antigen ; metabolism ; MicroRNAs ; metabolism ; Neoplasm Grading ; Neoplasm Staging ; Neprilysin ; metabolism ; Neuroendocrine Tumors ; classification ; diagnosis ; metabolism ; pathology ; surgery ; PAX8 Transcription Factor ; Paired Box Transcription Factors ; metabolism ; Pancreatic Neoplasms ; classification ; diagnosis ; metabolism ; pathology ; surgery ; Prognosis ; Tumor Suppressor Proteins ; metabolism

OBJECTIVETo investigate the protective effect of Crocin against hypoxia damage of cardiac myocytes of neonatal rats and the regulation of HIF-1 and prolyhydroxylase (PHDs).

METHODSA model of CoCl2 simulated hypoxia damage was established in primary cultural myocardial cell. Expression levels of HIF-1alpha, VEGF, iNOS, as well as PHD1, 2, 3 protein in myocardial cells were detected by Western blot.

RESULTSCompared with CoCl2 group, the viability of myocardial cell was significantly increased after treated 24 h at 10(-5)mol/L Crocin (P < 0.01), HIF-1alpha, VEGF and iNOS were expressed higher than those in Crocin + CoCl2 group (P < 0.01), the expression of PHD2 was significantly increased (P < 0.01), while the expression of PHD3 was remarkably reduced in Crocin + CoCl2 Group (P < 0.01).

CONCLUSIONCrocin has better protective effect on hypoxic damage of myocardial cell. The mechanisms of protective effect of Crocin may be related to the activation of HIF-1-mediated pathway of the hypoxia response. PHDs may be involved in the pathophysiology regulated process of myocardial cells.

Animals ; Carotenoids ; pharmacology ; Cell Hypoxia ; drug effects ; Cells, Cultured ; Homeodomain Proteins ; metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; metabolism ; Myocytes, Cardiac ; drug effects ; metabolism ; Nitric Oxide Synthase Type II ; metabolism ; Procollagen-Proline Dioxygenase ; metabolism ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A ; metabolism