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)

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia-reperfusion injury in infant rabbit heart. EPO (1.0 U/ml) administered 15 minutes prior to 30-minutes global ischemia and 35 minutes reperfusion resulted in increased recovery of postischemic ventricular developed pressure in rabbit hearts. EPO exerted its immediate cardioprotective effect via activation of multiple signaling pathways by: 1) phosphorylation and activation of JAK1/2, STAT3 and STAT5A but not of STAT1alpha and STAT5B, 2) phosphorylation and activation of PI(3) kinase and its downstream kinases Akt and Rac, 3) activation of PKCepsilon, Raf, MEK1/2, p42/44 MAPK and p38 MAPK. Pretreatment with Wortmannin abolished EPO-induced Akt activation and phosphorylation. Pretreatment with Chelerythrine followed by EPO treatment resulted in partial inhibition of Raf activation, and abolished PKCepsilon and p38 MAPK activation without any effect on Akt, MEK1/2 and p42/44 MAPK. PD98059 abolished MEK1/2 and p42/44 MAPK activation with no effect on Akt, Raf and p38 MAPK activation. SB203580 inhibited only p38 MAPK activation by EPO. We can conclude EPO increases immediate cardioprotection through the activation of multiple signal transduction pathways.
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PMID:Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. 1561 43

Normal tissue function depends on adequate supply of oxygen through blood vessels. Reduced oxygen supply (hypoxia) induces a variety of specific adaptation mechanisms in mammals that occur at the cellular, local and systemic level. These mechanisms are in part governed by the activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2. Prolyl and asparaginyl hydroxylases as recently characterized oxygen sensors allow the regulation of HIFs that in turn modulate expression of hypoxically regulated genes such as VEGF. VEGF plays a key role in the formation of a functional and integrated vascular network required during physiological processes such as embryogenesis or female reproductive cycle as well as during a variety of pathological processes such tumor growth, wound healing, retinopathy and ischemic diseases (myocardial infarction, cerebral ischemia). However, other angiogenic factors, such as angiopoietins, PDGF, ephrins and erythropoietin are additionally needed to enable the formation of a functional vascular network. Many of these factors are activated during hypoxia although no HIF binding sites have yet been identified in the regulatory sequences of theses genes. Hypoxia-induced gene products that result in new vessel growth may be part of a self-regulated physiological protection mechanism preventing cell injury, especially under conditions of chronically reduced blood blow (chronic ischemia).
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PMID:Angiogenesis--a self-adapting principle in hypoxia. 1561 78

Replacement of injured endothelial cells by bone marrow derived endothelial progenitor cells (EPC's) is a new pathway of vascular repair after ischemia. Endothelial progenitor cells contribute less than 0.01% to the peripheral venous compartment of mononuclear cells. The detection of EPC's requires a demonstration of CD 34 and VEGFR-2 (vascular endothelial growth factor receptor-2) antigenic cell membrane determinants and proof of endothelial characteristics after outgrowth and differentiation in cell culture. The most important stimuli to the mobilization and proliferation of EPC's are VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), erythropoietin, HMG-CoA-reductase inhibitors and tissue ischemia. In vivo in patients EPC's appear to contribute to endothelialization of vascular grafts, the formation of collaterals of ischemic limbs and the healing of myocardial infarcts. The role of EPC's in uremia is currently under investigation.
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PMID:Role of endothelial progenitor cells in cardiovascular pathology. 1563 37

Decreased blood flow is one of the earliest physiological changes observed after the onset of either clinical or experimental diabetes. The reduction in blood flow is believed to lead to nerve hypoxia, which in conjunction with other metabolic alterations and degenerative processes in different nerve compartments, results in the dysfunction known as diabetic neuropathy. The transcriptional regulator hypoxia-inducible factor-1 alpha (HIF-1alpha) accumulates rapidly under hypoxic conditions and modulates the expression of several target genes that protect tissues against ischemia and infarction. At present it is unclear whether diabetic nerve injury results from an abnormal response of HIF-1alpha and its protective target genes. In the present study we have analyzed the expression and activity of HIF-1alpha and its target genes in diabetic nerves as a first step to determine their possible contribution to the development or maintenance of diabetic neuropathy. We observed a transient increase in the expression of HIF-1alpha that peaked between 4 and 6 weeks and declined 8 weeks after induction of experimental diabetes in rats. The increase in HIF-1alpha in diabetic nerves coincided with a similarly transient increase in the expression of several HIF-1alpha target genes including vascular endothelial growth factor, lactate dehydrogenase and erythropoietin, which subsided 8-10 weeks after induction of diabetes. These results suggest that the transient activation of neurotrophic and angiogenic genes, as opposed to a more sustained effect in response to the chronic injury, may be responsible for the alterations in nerve function and regeneration that characterize the diabetic neuropathy.
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PMID:Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats. 1566 58

Delayed cerebral ischemia as a result of cerebral vasospasm is the most common cause of death and disability after aneurysmal subarachnoid hemorrhage (SAH). It leads to death or permanent neurologic deficits in over 17-40% of SAH patients. The initial and main symptom of cerebral vasospasm is diffuse headache and may be accompanied with a slight increase in discomfort from neck stiffness and fever. The clinical diagnosis of cerebral vasospasm is made when the patient experiences an altered level of consciousness or a new focal neurologic deficit. There has been a great progress in identifying the patients at risk, putative mechanisms, and possible treatment options for cerebral vasospasm. However, the problem is by no means solved, mainly due to a limited understanding of the pathologic mechanisms of this complex disease. The iatrogenic factors that can increase the risk of cerebral vasospasm include prolongation of the subarachnoid clot by antifibrinolytic drugs, hypotension, inappropriate treatment of hyponatremia, hypovolemia, hyperthermia and increased intracranial pressure. Nimodipine has been shown to improve neurologic outcome and decrease the incidence of cerebral vasospasm. Triple H therapy is a treatment designed to augment cerebral blood flow for patient with cerebral vasospasm. Hypervolemic hypertension is induced with intravenous volume expansion with crystalloid or colloid to increase cardiac output and raise blood pressure. However, small randomized trials showed no clear benefit. Recently, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators has emerged as the primary intervention for treating medically refractory ischemia from cerebral vasospasm and in many centers is being used as a first-line treatment or even prophylactically. In addition, promising new treatments for cerebral vasospasm or its ischemic complications include magnesium sulfate, fasudil hydrochloride, tirilazad mesylate, erythropoietin, and induced hypothermia; however, all still need further clinical trials. Newly recognized mediators of cerebral vasospasm after SAH include endothelium-derived mediators, vascular smooth-muscle-derived mediators, proinflammatory mediators involved in blood-brain barrier disruption, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Moreover, observations in the laboratory have, in many circumstances, matched those of reported small series. Larger, prospective, randomized trials are needed to verify several hypotheses of molecular pathophysiology and clinical treatment regimens.
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PMID:Treatment of cerebral vasospasm after subarachnoid hemorrhage--a review. 1567 31

Animals exposed to brief periods of moderate hypoxia (8% to 10% oxygen for 3 hours) are protected against cerebral and cardiac ischemia between 1 and 2 days later. This hypoxia preconditioning requires new RNA and protein synthesis. The mechanism of this hypoxia-induced tolerance correlates with the induction of the hypoxia-inducible factor (HIF), a transcription factor heterodimeric complex composed of inducible HIF-1alpha and constitutive HIF-1beta proteins that bind to the hypoxia response elements in a number of HIF target genes. Our recent studies show that HIF-1alpha correlates with hypoxia induced tolerance in neonatal rat brain. HIF target genes, also induced following hypoxia-induced tolerance, include vascular endothelial growth factor, erythropoietin, glucose transporters, glycolytic enzymes, and many other genes. Some or all of these genes may contribute to hypoxia-induced protection against ischemia. HIF induction of the glycolytic enzymes accounts in part for the Pasteur effect in brain and other tissues. Hypoxia-induced tolerance is not likely to be equivalent to treatment with a single HIF target gene protein since other transcription factors including Egr-1 (NGFI-A) have been implicated in hypoxia regulation of gene expression. Understanding the mechanisms and genes involved in hypoxic tolerance may provide new therapeutic targets to treat ischemic injury and enhance recovery.
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PMID:Hypoxic preconditioning protects against ischemic brain injury. 1571 5

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP-1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.
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PMID:Growth factor treatment of stroke. 1585 97

Ischemic preconditioning is a powerful endogenous phenomenon in which brief periods of a sub-toxic ischemic insult induce robust protection against future, lengthy, lethal ischemia. The cardioprotective effects of ischemic preconditioning are manifest in all species studied so far, including humans. The ability to reproduce the cardioprotective effects of ischemic preconditioning with pharmacological agents raises the possibility that a drug may ultimately be introduced into clinical practice to treat human hearts undergoing ischemia/reperfusion. This chapter focuses on erythropoietin (Epo), a drug that has already been approved for humans and is in current use for the treatment of anemia associated with chronic renal failure, HIV infection, cancer patients on chemotherapy, and to reduce allogenic blood transfusion in surgery patients. Several recent studies have suggested that this cytokine possesses properties far beyond its capacity to produce red blood cells such as the ability to protect tissues including brain, kidney and heart against injury caused by ischemia/reperfusion. Cardioprotection conferred by Epo has been shown to be equal in magnitude to that conferred by ischemic preconditioning. However, the underlying mechanisms by which Epo protects the heart against injury caused by ischemia remain unknown.
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PMID:Erythropoietin mimics ischemic preconditioning. 1592 56

Treatment with deferoxamine (DFO) is protective against focal ischemia with global hypoxia when given as a preconditioning stimulus in neonatal rodents. DFO acts as an iron chelator and may stabilize HIF1alpha. Therefore, we hypothesized that DFO would protect against pure ischemia-reperfusion injury when given after the insult and that the protection would be associated with expression of hypoxia-inducible factor 1alpha (HIF1alpha) and downstream target genes such as erythropoietin (Epo). To test these hypotheses, we performed middle cerebral artery (MCA) occlusion in postnatal day 10 (P10) rats for 1.5 h followed by treatment with DFO or vehicle upon reperfusion. Preserved brain volumes were measured with cresyl violet staining 1 week after the insult. HIF1alpha and Epo expression were determined by Western blot and immunocytochemical analyses at different time points after injury. We found that DFO treatment preserved brain volumes when compared to vehicle (P < 0.05). In DFO-treated ischemic cortices, HIF1alpha expression peaked early, while Epo expression was seen in two phases and in different cell populations. Epo immunoreactivity colocalized with neuronal markers at 8 h but with astrocytic markers at 1 week. These results suggest that DFO is protective when administered after neonatal ischemic stroke and that this protection may be like that afforded by preconditioning through the upregulation of similar downstream pathways.
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PMID:Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke. 1602 39

Erythropoietin (epo), initially recognized and used clinically to increase erythropoiesis, has been shown to have beneficial effects on various other tissues in the setting of hypoxia and ischemia. Epo has been shown to reduce apoptosis after myocardial infarction, but few studies have evaluated the long-term effects of epo treatment on left ventricular (LV) remodeling, cardiac function, and blood flow after healing of a permanent coronary artery occlusion. The aim of this study was to assess the effects of epo treatment on the healed heart 6 weeks after myocardial infarction. Anesthetized rats underwent coronary artery occlusion and were treated with erythropoietin (5000 units/kg/day, n=21) or saline (n=20) the day before surgery, the day of, then for 5 days. At 6 weeks LV ventriculography to assess LV volumes and ejection fractions and histologic assessment of infarct size and LV cavity and wall dimensions were performed. Overall epo had no effect on LV remodeling or cardiac function. There were no significant differences in infarct morphology, infarct size (44+/-3% of the LV circumference versus 39+/-3%), LV cavity area, scar thickness, LV systolic volume, or ejection fraction (44+/-3% versus 39+/-3%) between the epo and saline groups, respectively. However, for any given size of myocardial infarct, LV ejection fraction was significantly higher in erythropoietin hearts and LV systolic volumes lower. Thus, in our model, treatment with epo had no long-term beneficial effect on LV remodeling after myocardial infarction but may have exerted some positive effect on LV function.
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PMID:Administration of erythropoietin fails to improve long-term healing or cardiac function after myocardial infarction in the rat. 1604 33


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