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

We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in EpoR(-/-)-rescued mice that lack EpoR in most organs including cardiovascular system except erythroid-lineage cells. Two weeks after femoral artery ligation, blood flow recovery, activation of VEGF/VEGF receptor system, and mobilization of endothelial progenitor cells were all impaired in EpoR(-/-)-rescued mice as compared with wild-type (WT) mice. Bone marrow (BM) transplantation with WT-BM cells in EpoR(-/-)-rescued mice partially but significantly improved blood flow recovery after hindlimb ischemia. The extent of VEGF upregulation and the number of BM-derived cells in ischemic tissue were significantly less in EpoR(-/-)-rescued mice compared with WT mice even after BM reconstitution with WT-BM cells. Similarly, the recovery of blood flow was significantly impaired in recipient EpoR(-/-)-rescued mice that had been transplanted with WT-BM or EpoR(-/-)-rescued-BM as compared with recipient WT mice. Furthermore, the Matrigel implantation assay and aortic ring assay showed that microvessel growth in vitro was significantly reduced in EpoR(-/-)-rescued mice as compared with WT mice. These results indicate that vascular EpoR system also plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of VEGF/VEGF receptor system, both directly by enhancing neovascularization and indirectly by recruiting endothelial progenitor cells and BM-derived proangiogenic cells.
 ...
PMID:Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. 1736 4

Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting of 165 amino acids produced mainly in the kidney and in the liver and regulating erythrocyitosis. It primarily acts on erythroid precursor cell at colony-forming units-erythroid stage inhibiting the apoptosis. EPO binds on a specific membrane receptor thereby activating at least three specific intracellular signaling pathways, such as phosphatidylinositol 3-kinase/ protein kinase B, Ras-mitogen-activated protein kinase and some members of the signal transducers and activators of transcription family. In addition to kidney and liver, EPO mRNA has been detected in other tissues; accordingly EPO receptor has been identified in several type of cells and recent reports have suggested new roles for EPO in non-haematopoietic tissues with a robust evidence for neuroprotective and cardioprotective activity. In different animal models, in vitro, in isolated perfused heart and in vivo, recombinant human erythropoietin protects heart from ischemia reperfusion injury and reduces myocardial damage. EPO tissue protective activity can be separated from erythropoietic activity. Molecules owing the first property but not the second one have been described. In patients with acute myocardial infarction serum EPO level correlates inversely with infarct size. Acute coronary syndrome, extracorporeal circulation and percutaneous coronary intervention are potential fields of application for tissue protective EPO activity to reduce myocardial damage, increase cardiac function ad improve outcome.
 ...
PMID:Structure, production and function of erythropoietin: implications for therapeutical use in cardiovascular disease. 1789 76

Erythropoietin (EPO), a renal cytokine, regulates proliferation, differentiation and maturation of erythroid cells. Recombinant human erythropoietin (rH-EPO) is well known to correct anemia in patients with chronic renal failure undergoing dialysis. Recent studies have reported several non-hematopoietical effects of EPO. Erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system. Recently published data including recent patent documented an enhancement of cardiac function in patients with heart failure receiving EPO treatment. Furthermore, experiments carried out in animal models of ischemia/reperfusion (IR) injury have shown a significant reduction in infarct size following EPO treatment. Other beneficial effects of EPO are related to its pro-angiogenic action on endothelial cells, which might be of potential value in patients with ischemic heart disease. Taken together, these findings suggest that EPO may be clinically useful as an adjunct in the treatment of different cardiovascular conditions, besides the simple correction of anemia. This review will focus on the pleiotropic effects of EPO in the cardiovascular system and its promising novel applications.
 ...
PMID:Erythropoietin: new horizon in cardiovascular medicine. 1822 Oct 97

Erythropoietin is a hypoxia-induced cytokine that stimulates erythropoiesis through the promotion of erythroid precursor cell proliferation and differentiation. Recent evidence supports that erythropoietin has a broad spectrum of tissue protecting actions affecting other systems than hemopoietic. Lately, research has focused on the nonhemopoietic effects of erythropoietin against tissue ischemia due to the unexpected observations of erythropoietin receptor expression by various cells, such as endothelial cells, neuronal cells, cardiac myocytes, and vascular smooth muscle cells. It has been shown that erythropoietin exerts its cardioprotective action during cardiac ischemic injury through reducing the infract size and enhancing new vessel formation over a longer time frame. Erythropoietin plays a crucial role in neuroprotection in many types of ischemic injury in the central and the peripheral nervous system. It is also strongly believed that erythropoietin exhibits a critical role in many other disorders that are pathogenetically related to acute tissue ischemia. This article reviews the proposed implications of erythropoietin in tissue ischemia and discusses the possible mechanisms for this action along with its potential therapeutic applications.
 ...
PMID:The role of erythropoietin as an inhibitor of tissue ischemia. 1856 95

Erythropoietin (Epo) is a hematopoietic factor, which stimulates proliferation and differentiation of erythroid precursor cells. Epo also functions as a neuroprotective factor and protects neurons from ischemic damage. Recently a 17-mer peptide sequence (Epopeptide AB) in Epo (AEHCSLNENITVPDTKV) with a neuroprotective function was reported. In this study, we showed in vivo evidence that Epopeptide AB protected neurons from ischemic damage at similar dose compared to Epo. Epopeptide AB could not stimulate the proliferation of Epo-dependent growing murine myeloid Ep-FDC-P2 cells and also did not compete the proliferative function of Epo on these cells. Together with these results, Epopeptide AB did not transduce signals through direct binding to the known Epo receptor on hematopoietic cells but has neuroprotective activity against ischemia.
 ...
PMID:In vivo Neuroprotective Activity of Epopeptide AB Against Ischemic Damage. 1900 54

The development of cell therapies to treat peripheral vascular disease has proven difficult because of the contribution of multiple cell types that coordinate revascularization. We characterized the vascular regenerative potential of transplanted human bone marrow (BM) cells purified by high aldehyde dehydrogenase (ALDH(hi)) activity, a progenitor cell function conserved between several lineages. BM ALDH(hi) cells were enriched for myelo-erythroid progenitors that produced multipotent hematopoietic reconstitution after transplantation and contained nonhematopoietic precursors that established colonies in mesenchymal-stromal and endothelial culture conditions. The regenerative capacity of human ALDH(hi) cells was assessed by intravenous transplantation into immune-deficient mice with limb ischemia induced by femoral artery ligation/transection. Compared with recipients injected with unpurified nucleated cells containing the equivalent of 2- to 4-fold more ALDH(hi) cells, mice transplanted with purified ALDH(hi) cells showed augmented recovery of perfusion and increased blood vessel density in ischemic limbs. ALDH(hi) cells transiently recruited to ischemic regions but did not significantly integrate into ischemic tissue, suggesting that transient ALDH(hi) cell engraftment stimulated endogenous revascularization. Thus, human BM ALDH(hi) cells represent a progenitor-enriched population of several cell lineages that improves perfusion in ischemic limbs after transplantation. These clinically relevant cells may prove useful in the treatment of critical ischemia in humans.
 ...
PMID:Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. 1932 6

Oxidative stress is involved in acute kidney injury due to ischemia-reperfusion and chemotherapy-induced nephrotoxicity. To investigate their basic mechanisms we studied the role of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2), a redox-sensitive transcription factor that regulates expression of several antioxidant and cytoprotective genes. We compared the responses of Nrf2-knockout mice and their wild-type littermates in established mouse models of ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. Several Nrf2-regulated genes encoding antioxidant enzymes/proteins were significantly upregulated in the kidneys of wild type but not Nrf2-knockout mice following renal ischemia. Renal function, histology, vascular permeability, and survival were each significantly worse in the Nrf2 knockout mice. Further, proinflammatory cytokine and chemokine expression tended to increase after ischemia in the knockout compared to the wild-type mice. Treatment of the knockout mice with the antioxidants N-acetyl-cysteine or glutathione improved renal function. The knockout mice were more susceptible to cisplatin-induced nephrotoxicity, and this was blunted by N-acetyl-cysteine pretreatment. Our study demonstrates that Nrf2-deficiency enhances susceptibility to both ischemic and nephrotoxic acute kidney injury, and identifies this transcription factor as a potential therapeutic target in these injuries.
 ...
PMID:Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. 1943 34

CLP-1, the mouse homologue of human Hexim1 protein, exerts inhibitory control on transcriptional elongation factor-b of RNA transcript elongation. Previously, we have demonstrated that downregulation of cardiac lineage protein-1 (CLP-1) in CLP-1(+/-) heterozygous mice affords cardioprotection against ischemia-reperfusion injury. Our current study results show that the improvement in cardiac function in CLP-1(+/-) mice after ischemia-reperfusion injury is achieved through the potentiation of redox signaling and their molecular targets including redox effector factor-1, nuclear factor erythroid 2-related factor, and NADPH oxidase 4 and the active usage of thioredoxin-1, thioredoxin-2, glutaredoxin-1 and glutaredoxin-2. Our results suggest that drugs designed to down regulate CLP-1 could confer cardioprotection through the potentiation of redox cycling.
 ...
PMID:Downregulation of cardiac lineage protein-1 confers cardioprotection through the upregulation of redox effectors. 1993 34

Angiogenesis therapy by bone marrow-mononuclear cell implantation (BMI) has been utilized. We found that erythroid cells played an essential role in angiogenesis by BMI. We then tried to establish a novel cell therapy by implantation of ex vivo expanded immature erythroblasts cultured from hematopoietic stem/precursor cells. Immature to mature erythroblasts were purified from human bone marrow, and mRNA expression were analyzed. Strongly expressed VEGF and PLGF in immature erythroid cells decreased according to erythroid maturation. To expand very immature erythroid cells, we established a two-step culturing system, i.e., bone marrow cells were cultured in the presence of Flt-3L, SCF and TPO for 7 days, and the cells were further cultured in the presence of SCF, IGF-I and EPO for an additional 7 days. The in vivo angiogenic effects of implantation of the ex vivo expanded cells were stronger than that of BMI in mouse limb ischemia model. Three patients with severe chronic lower limb ischemia accompanied by Burger's disease or collagen arteritis were enrolled in a pilot clinical trial of the novel cell therapy by transplantation of ex-vivo expanded immature erythroid cells. In the clinical trial, most clinical symptoms such as rest pain and skin ulcers improved in 4 weeks, and did not recur in the one-year follow-up. No adverse events were observed in any of the patients. Moreover this novel cell therapy required only a small amount of bone marrow collection. Further enrollment of patients with chronic severe lower limb ischemia is necessary to confirm the efficacy and safety of this novel cell therapy, and to estimate the necessary amount of bone marrow aspirate.
 ...
PMID:Establishment of culturing system for ex-vivo expansion of angiogenic immature erythroid cells, and its application for treatment of patients with chronic severe lower limb ischemia. 2055 29

The erythropoietin is produced by the kidney and other organs. EPO does not only affect erythroid cells, but also other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytes function of the polymorph nuclear cells and reduces the activation of macrophages, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors also on mesangial and myocardial cells and smooth muscle fibro-cells has prompted the study of the pleiotropic actions of this hormone. Through its receptors, spread out over the body, it carries out many actions which range from the erythrogenesis after hypoxic stimuli to the tissue protection of the heart and the brain after ischemia. Erythropoietin also acts in the endothelial proliferation of new vessels involving the tumor genesis, but it opens new frontiers to the employment of rHuEPO in the Regenerative Medicine.
 ...
PMID:[Erythropoietin: pleiotropic actions]. 2067 74


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>