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 G-protein-coupled receptors of the endothelial differentiation gene (EDG) family mediate pro-angiogenic activities, such as endothelial cell proliferation, chemotaxis, and vessel morphogenesis. We synthesized and tested the effects of a 9-amino acid peptide (KRX-725), derived from the second intracellular loop of S1P3 (EDG3). KRX-725 mimics the effects of sphingosine 1-phosphate (S1P), the natural ligand of S1P3, by triggering a Gi-dependent MEK-ERK (mitogen-activated protein kinase kinase and extracellular signal-regulated kinase) signal transduction pathway. Using aortic rings as an ex vivo model of angiogenesis, vascular sprouting was assessed in the presence of KRX-725 or S1P. KRX-725 induced extensive and dense vascular sprouts, which contain an elaborated organization of endothelial and smooth muscle layers, including lumen formation. When KRX-725 or S1P was combined with proangiogenic factors, such as basic fibroblast growth factor (bFGF), stem cell factor, or vascular endothelial growth factor, the effect was synergistic, leading to further enhancement of vascular sprouting. KRX-725 also initiated neovascularization in a mouse corneal pocket assay in vivo and showed synergism with bFGF. The specificity of KRX-725 was demonstrated via peptide-induced receptor internalization of S1P3 but not S1P1. The ability of a short peptide to stimulate extensive angiogenesis and to synergize with pro-angiogenic factors suggests that KRX-725 may serve as a useful agent in treating pathologic conditions such as peripheral vascular disease, cardiac ischemia, or tissue grafts.
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PMID:Induction of pro-angiogenic signaling by a synthetic peptide derived from the second intracellular loop of S1P3 (EDG3). 1276 36

The heart is subjected to oxidative stress during various clinical situations, such as ischemia-reperfusion injury and anthracycline chemotherapy. The loss of cardiac myocytes is the major problem in heart failure; thus, it is important to protect cardiac myocytes against cell death. Various growth factors, including insulin like growth factor, hepatocyte growth factor, endothelin-1, fibroblast growth factor, and transforming growth factor, have been shown to protect the heart against oxidative stress. The mechanism of growth factor-mediated cardioprotection may involve the attenuation of cardiac myocyte apoptosis. The present article summarizes the current knowledge on the molecular mechanisms of growth factor-mediated antiapoptotic signaling in cardiac myocytes. Insulin-like growth factor-1 activates phosphatidylinositol 3' -kinase and extracellular signal-regulated kinase pathways. Recent data showed that GATA-4 might be an important mediator of cardiac myocyte survival by endothelin-1 and hepatocyte growth factor. These growth factors, as well as mediators of growth factor-signaling, may be useful in therapeutic strategies against oxidative stress-induced cardiac injury.
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PMID:Growth factor signaling for cardioprotection against oxidative stress-induced apoptosis. 1458 47

Extracellular hypertonicity can induce the phosphorylation of mitogen-activated protein kinases (MAPKs). Of these, both extracellular signal-regulated kinases (ERKs) and the stress-activated kinase p38 have been implicated in neuronal cell survival. Resuscitation with hypertonic saline decreases secondary brain injury after trauma, as well as neuronal damage, after ischemia. Since hypertonicity has been shown to support somatic cell survival, we investigated if hypertonicity can also prevent neuronal cell death via MAPK signaling. Death of postnatal rat corticospinal motoneurons (CSMNs) was induced by serum deprivation, and survival in both isotonic and hypertonic media was assessed after 20 h. Addition of NaCl (4-250 mM) to isotonic medium significantly and dose dependently protected CSMN in enriched cultures, increasing cell survival by up to 70% over that in isotonic medium. This response was not restricted to NaCl; addition of KCl, choline chloride, and sucrose had similar effects on cell survival. In addition, hypertonicity supported the survival of pure CSMN populations, albeit with lower potency. In cortical cell suspensions, hypertonic NaCl (20-100 mM) increased basal phosphorylation of p38 and ERK. The activation of both MAPKs, which was induced by 40 mM NaCl, was transient. Cultivation of CSMNs in media containing the specific p38 inhibitor SB203580 abolished the protective effect of hypertonic NaCl, indicating a central role for p38. We therefore conclude that hypertonicity can prevent neuronal cell death via MAPK signaling.
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PMID:Hypertonicity promotes survival of corticospinal motoneurons via mitogen-activated protein kinase p38 signaling. 1459 11

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.
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PMID:A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia. 1466 49

Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic (plasma glucose approximately 20 mM) and hypercapnic (paCO2) approximately 300 mm Hg) global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCgamma, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes, as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCgamma, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cingulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.
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PMID:Hyperglycemia and hypercapnia differently affect post-ischemic changes in protein kinases and protein phosphorylation in the rat cingulate cortex. 1467 11

Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (+/-)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H(2)O(2)-stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 microM H(2)O(2), indicating that exogenous 500 microM H(2)O(2) was a growth stimulator of rat aortic smooth muscle cells. Exogenous H(2)O(2) significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells (IC(50): 200 microM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H(2)O(2) in a dose-dependent manner. In 500 microM H(2)O(2)-stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 microM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H(2)O(2)-stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.
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PMID:Antiproliferative mechanisms of raxofelast (IRFI-016) in H2O2-stimulated rat aortic smooth muscle cells. 1474 95

Although c-Jun NH(2)-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-kappaB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4 degrees C for 4 h followed by reperfusion at 37 degrees C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-kappaB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-alpha into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.
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PMID:Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs. 1476 30

Mitogen-activated protein kinases are serine-threonine protein kinases that are involved in several processes important to cardiac surgery such as vascular permeability, cytokine production, vasomotor function, and reperfusion injury. Mitogen-activated protein kinases are expressed in multiple cell types including cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Mitogen-activated protein kinases function in cellular signal transduction cascades and are activated by a diverse range of stimuli including ischemia, shear stress, and vasoactive agents. Three major mitogen-activated protein kinase families were identified as the extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases. Extensive investigation has established roles for extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases in cardiovascular signal transduction pathways. Activity of these signal cascades may contribute to the increased pulmonary vascular permeability and myocardial reperfusion injury observed after cardiac surgery with cardioplegia and cardiopulmonary bypass. Recent findings from our laboratory suggest that alterations in the activity of myocardial extracellular signal-regulated kinase pathways occur as a result of cardioplegia-cardiopulmonary bypass in humans. In addition, these differences in extracellular signal-regulated kinase activity were shown to mediate coronary microcirculatory dysfunction associated with cardioplegia-cardiopulmonary bypass. The resulting deficit in coronary microcirculatory regulation may potentially lead to detrimental effects on organ perfusion and function. As mitogen-activated protein kinase pathways are further characterized, our potential to develop methods to prevent morbidity associated with cardiac surgery and cardiopulmonary bypass may be greatly improved.
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PMID:Mitogen-activated protein kinase pathways and cardiac surgery. 1500 10

Ischemic preconditioning (IPC) is a most powerful endogenous mechanism for myocardial protection against ischemia/reperfusion injury. It is now apparent that reactive oxygen species (ROS) generated in the mitochondrial respiratory chain act as a trigger of IPC. ROS mediate signal transduction in the early phase of IPC through the posttranslational modification of redox-sensitive proteins. ROS-mediated activation of Src tyrosine kinases serves a scaffold for interaction of proteins recruited by G protein-coupled receptors and growth factor receptors that is necessary for amplification of cardioprotective signal transduction. Protein kinase C (PKC) plays a central role in this signaling cascade. A crucial target of PKC is the mitochondrial ATP-sensitive potassium channel, which acts as a trigger and a mediator of IPC. Mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun NH(2)-terminal kinase) are thought to exist downstream of the Src-PKC signaling module, although the role of MAP kinases in IPC remains undetermined. The late phase of IPC is mediated by cardioprotective gene expression. This mechanism involves redox-sensitive activation of transcription factors through PKC and tyrosine kinase signal transduction pathways that are in common with the early phase of IPC. The effector proteins then act against myocardial necrosis and stunning presumably through alleviation of oxidative stress and Ca(2+) overload. Elucidation of IPC-mediated complex signaling processes will help in the development of more effective pharmacological approaches for prevention of myocardial ischemia/reperfusion injury.
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PMID:Reactive oxygen species as mediators of signal transduction in ischemic preconditioning. 1502 47

Excessive production of nitric oxide (NO) in the central nervous system (CNS) mediated by activation of microglia has been implicated in neurotoxicity after stresses such as ischemia. Baicalein, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, anticarcinogenic, and neuroprotective effects. In the present study, we report the inhibitory effect of baicalein on endotoxin/cytokine-induced NO production and inducible nitric oxide synthase (iNOS) gene expression in microglia. Baicalein abolished the endotoxin/cytokine-induced expression of iNOS protein, iNOS mRNA, and iNOS promoter activity in a parallel concentration-dependent manner. The suppression of iNOS expression was not mediated through the down-regulation of tumor necrosis factor-alpha (TNF-alpha) by baicalein because TNF-alpha failed to enhance endotoxin/cytokine-induced NO production in microglia. From the electrophoretic mobility shift assay (EMSA), we found that baicalein exerted a distinct inhibitory effect on the DNA binding activity of transcription factors, and this was significantly greater in nuclear factor IL-6 (NF-IL6) than in nuclear factor kappa B (NF-kappaB) and activated protein 1 (AP-1). Although extracellular signal-regulated kinase (ERK) is critical to iNOS expression, endotoxin/cytokine-stimulated phosphorylation of ERK1/2 was not significantly inhibited by baicalein. These results indicate that NF-IL6 inactivation could be the major determinant for the suppression of NO production by baicalein in microglia. Furthermore, it suggests that the inhibitory effect of baicalein on microglia activation and neurotoxic factor production is responsible for its neuroprotective action.
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PMID:Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia. 1510 49


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