Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (EPO), already known as the stimulating hormone for erythropoiesis, has shown different and interesting pleiotropic actions. It does not only affect erythroid cells, but also myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytic function of the polymorphonuclear cells and reduce the activation of macrophages, thus modulating the inflammatory process.Moreover, hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors (EPO-R) also on mesangial and myocardial cells, smooth muscle fibrocells and neurons has prompted the study of the non-erythropoietic functions of this hormone.The interaction between EPO and VEGF may be of particular importance in neovascularization and wound healing. Different studies have demonstrated that EPO has an important direct hemodynamic and vasoactive action, which does not depend exclusively on any increase in hematocrit and viscosity. Moreover EPO showed protective effects on myocardial cells against apoptosis induced by ischemia/repefusion injury, but it could negatively affect pulmonary hypertension in patient with chronic cor pulmonale.This review aims to stress the importance of the increasing interest in EPO applications and the necessity of further studies to gain a deeper knowledge of this hormone and its pleiotropic and complex actions.
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PMID:From the oxygen to the organ protection: erythropoietin as protagonist in internal medicine. 1707 7

Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells and cardiomyocytes. In animal studies, treatment with EPO during ischemia/reperfusion in the heart has been shown to limit the infarct size and the extent of apoptosis. In the longer term, EPO may promote ischemia-induced neovascularization, either by stimulating endothelial cells in situ or by mobilizing endothelial progenitor cells from bone marrow. The effects of EPO in the ischemic heart support the concept of EPO as a pleiotropic, tissue-protective agent for other organs expressing the EPO receptor. We recently performed a first randomized clinical study showing the safety and feasibility of EPO administration in patients with acute myocardial infarction. Future clinical studies are warranted to translate the beneficial effects of EPO from basic experiments to cardiac patients.
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PMID:Protective effects of erythropoietin in cardiac ischemia: from bench to bedside. 1716 Dec 40

Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia-reperfusion (I/R) injury of the brain, heart, and kidney. However, whether EPO exerts its protection by prevention of postischemic microcirculatory deterioration is unknown. We have investigated the effect of EPO on I/R-induced microcirculatory dysfunctions. We used the mouse dorsal skinfold chamber preparation to study nutritive microcirculation and leukocyte-endothelial cell interaction in striated muscle of the dorsal skinfold by in vivo fluorescence microscopy before 3 h of ischemia and during 5 days of reperfusion. Animals were pretreated with EPO (5,000 U/kg body wt) 1 or 24 h before ischemia. Vehicle-treated I/R-injured animals served as controls. Additional animals underwent sham operation only or were pretreated with EPO but not subjected to I/R. I/R significantly (P < 0.05) reduced functional capillary density, increased microvascular permeability, and enhanced venular leukocyte-endothelial cell interaction during early reperfusion. These findings were associated with pronounced (P < 0.05) arteriolar constriction and diminution of blood flow during late reperfusion. Pretreatment with EPO induced EPO receptor and endothelial nitric oxide synthase expression at 6 h of reperfusion (P < 0.05). In parallel, EPO significantly (P < 0.05) reduced capillary perfusion failure and microvascular hyperpermeability during early reperfusion and arteriolar constriction and flow during late reperfusion. EPO pretreatment substantially (P < 0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. EPO applied 1 h before ischemia induced angiogenic budding and sprouting at 1 and 3 days of reperfusion and formation of new capillary networks at 5 days of reperfusion. Thus our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic inflammation, and inducing new vessel formation.
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PMID:Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice. 1733 94

The purpose of this study was to evaluate whether the concentration of erythropoietin as another potent ischemia-induced angiogenic factor is elevated in eyes with neovascular (age-related macular degeneration [AMD]) or oedematous (diabetic retinopathy) maculopathies. The clinical comparative study included 28 patients with diabetic macular oedema, 59 patients with exudative AMD, and 49 patients with cataract. For all patients, aqueous humour was collected during cataract surgery or during an intravitreal injection of triamcinolone acetonide. Erythropoietin levels were measured using a solid-phase chemiluminescence immunoassay. The mean concentration of erythropoietin was significantly higher in the diabetic group (60.1 +/- 46.7 mUnits/mL; P < 0.001) than in the age-related macular degeneration group (22.9 +/- 23.2 mUnits/mL) and in the control group (22.0 +/- 21.0 mUnits/mL; P < 0.001). The two latter groups did not vary significantly (P = 0.41). The results indicate that erythropoietin may be present in considerably higher concentrations in eyes with diabetic macular oedema than in eyes with exudative AMD or normal eyes.
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PMID:Erythropoietin levels in aqueous humour in eyes with exudative age-related macular degeneration and diabetic retinopathy. 1736 63

Recent studies have suggested that the brain preconditioning could induce tolerance to ischemia in humans. It has been believed that newly synthesized proteins are required for the acquisition of delayed tolerance in the brain and spinal cord. However, the mechanism other than the synthesis of neuroprotective proteins may also play a pivotal role. Preconditioning may reprogram the response to ischemic injury as seen during hibernation. Preconditioning with hyperbaric oxygen, volatile anesthetics, and xenon seems to be the focus of the attention from the standpoint of the clinical setting. Strong neuroprotection by the preconditioning with isoflurane and xenon is reported in animal experiments and may change the traditional idea of neuroprotection by anesthetics. The discovery that erythropoietin exerts neuroprotective properties has opened new therapeutic avenues. Erythropoietin is induced in the brain by hypoxic preconditioning and by the pharmacological preconditioning. In addition, the intravenous administration of erythropoietin has been shown to be safe and beneficial for acute stroke in humans. Therefore, erythropoietin is now one of the most promising neuroprotective agents. The research in the brain and spinal cord preconditioning will contribute to the elucidation of the mechanism of ischemic injury and to the establishment of new therapies for neuroprotection.
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PMID:[Brain and spinal cord preconditioning for the protection against ischemic injury]. 1736 16

Endothelial progenitor cell (EPC) transplantation has beneficial effects for therapeutic neovascularization; however, only a small proportion of injected cells home to the lesion and incorporate into the neocapillaries. Consequently, this type of cell therapy requires substantial improvement to be of clinical value. Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors and their ephrin ligands are key regulators of vascular development. We postulated that activation of the EphB4/ephrin-B2 system may enhance EPC proangiogenic potential. In this report, we demonstrate in a nude mouse model of hind limb ischemia that EphB4 activation with an ephrin-B2-Fc chimeric protein increases the angiogenic potential of human EPCs. This effect was abolished by EphB4 siRNA, confirming that it is mediated by EphB4. EphB4 activation enhanced P selectin glycoprotein ligand-1 (PSGL-1) expression and EPC adhesion. Inhibition of PSGL-1 by siRNA reversed the proangiogenic and adhesive effects of EphB4 activation. Moreover, neutralizing antibodies to E selectin and P selectin blocked ephrin-B2-Fc-stimulated EPC adhesion properties. Thus, activation of EphB4 enhances EPC proangiogenic capacity through induction of PSGL-1 expression and adhesion to E selectin and P selectin. Therefore, activation of EphB4 is an innovative and potentially valuable therapeutic strategy for improving the recruitment of EPCs to sites of neovascularization and thereby the efficiency of cell-based proangiogenic therapy.
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PMID:PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells. 1751 Jul 5

Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction.
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PMID:Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms. 1757 97

Erythropoietin (Epo) has anti-apoptotic and pro-angiogenic effects in rodent models of myocardial infarction (MI). We tested the hypothesis that a long-acting Epo derivative (darbepoetin) has a beneficial effect on infarct size and peri-infarct remodeling in a clinically relevant large animal model of ischemia-reperfusion. A human acute MI scenario was simulated in 16 domestic pigs by inflating an angioplasty balloon in the proximal left circumflex (LCx) artery for 60 min. The animals were randomized to darbepoetin 30 microg/kg i.v. or placebo (saline) at the time of reperfusion. Treatment with darbepoetin did not lead to a reduction in the infarct size at 2 weeks as assessed by histology (30.3+/-1.8% of the volume at risk for placebo vs. 33.2+/-2.5% for darbepoetin). However, significant effects were seen in the peri-infarct region. Histological evaluation revealed decreased interstitial fibrosis (6.8+/-0.7% of myocardial sections area vs. 9.6+/-0.7%, p=0.02) and increased average capillary area (106+/-3% of the non-infarcted myocardium vs. 89+/-4%, p=0.003) in the treatment arm in the absence of significant cardiac hypertrophy. This resulted in preserved regional wall motion as assessed by tissue Doppler-derived radial strain (subepicardial radial strain 90.1+/-21.2% for darbepoetin vs. 20.3+/-10.1% for placebo, p<0.05). However, this did not translate to improved wall thickening (126.5+/-6.0% of diastolic thickness for darbepoetin vs. 119.8+/-5.4% for placebo, p=NS). Beneficial effects of darbepoetin to peri-infarct remodeling were observed in a clinically relevant model of ischemia-reperfusion. Although the infarct size was not reduced, there was a limited decrease in interstitial fibrosis, increased capillary area and regional functional improvement in darbepoetin-treated animals.
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PMID:Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion. 1759 49

Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoR-null mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extra-hematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.
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PMID:Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. 1760 82

Testicular torsion is an important clinical urgency. Similar mechanisms occurred after detorsion of the affected testis as in the ischemia reperfusion (I/R) damage. This study was designed to investigate the effects of erythropoietin (EPO) treatment after unilateral testicular torsion. Fifty male Sprague-Dawley rats were divided into five groups. Group 1 underwent a sham operation of the right testis under general anesthesia. Group 2 was same as sham, and EPO (3,000 IU/kg) infused i.p., group 3 underwent a similar operation but the right testis was rotated 720 degrees clockwise for 1 h, maintained by fixing the testis to the scrotum, and saline infused during the procedure. Group 4 underwent similar torsion but EPO was infused half an hour before the detorsion procedure, and in group 5, EPO was infused after detorsion procedure. Four hours after detorsion, ipsilateral and contralateral testes were taken out for evaluation. Treatment with EPO improved testicular structures in the ipsilateral testis but improvement was less in the contralateral testis histologically, but EPO treatment decreased germ cell apoptosis in both testes following testicular IR. TNF-alpha, IL-1beta, IL-6 and nitrite levels decreased after EPO treatment especially in the ipsilateral testis. We conclude that testicular I/R causes an increase in germ cell apoptosis both in the ipsilateral and contralateral testes. Erythropoietin has antiapoptotic and anti-inflammatory effects following testicular torsion.
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PMID:Protective role of erythropoietin during testicular torsion of the rats. 1769 Aug 91


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