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)

Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N-methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K(+) channel (K(ATP)) inhibitor glibenclamide (GLIB) or the mitochondrial K(ATP) (mitoK(ATP)) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK(ATP) activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 micromol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase (MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK(ATP) and p42/p44 MAPK.
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PMID:Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway. 1534 65

Little is known about the regulation mechanism of endothelial cell proliferation by retinal pericytes. The purpose of this study was to elucidate the suppression mechanism of retinal capillary endothelial cell growth by soluble factors derived from retinal pericytes. Conditioned medium of retinal pericytes (rPCT1-CM) suppressed ischemia-induced retinal neovascularization. The growth and DNA synthesis of TR-iBRB2 cells, a conditionally immortalized rat retinal capillary endothelial cell line, were suppressed in a concentration-dependent manner by concentrated rPCT1-CM. The number of human cultured endothelial cells was also reduced by rPCT1-CM. These results provide the first evidence that CM from the cultivation of pericytes alone can inhibit retinal neovascularization in vivo and in vitro. Although the growth reduction of TR-iBRB2 cells was only partly reversed by treatment of rPCT1-CM with antibodies to transforming growth factor-beta1, it was completely lost by heat-treatment of rPCT1-CM, suggesting that anti-angiogenic factors are soluble proteins. The levels of expression of G1/S-phase-related proteins, such as cyclin D1, cyclin-dependent kinase (cdk)4, cdk6, and proliferating cell nuclear antigen, were reduced and a cdk inhibitor, p21(Cip1), was induced in rPCT1-CM-treated TR-iBRB2 cells. Moreover, phosphorylated p44/42 mitogen-activated protein kinase (p44/42 MAPK) in TR-iBRB2 cells was reduced by rPCT1-CM treatment and phosphorylated protein kinase C (PKC)alpha/betaII, which is upstream of p44/42 MAPK, was also suppressed. In conclusion, CM from retinal pericytes suppresses PKC-p44/42 MAPK signaling, inhibits endothelial cell growth, and prevents retinal neovascularization. Anti-angiogenic factors derived from retinal pericytes are likely to play a critical role in the regulation of retinal endothelial cell growth.
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PMID:PKC/MAPK signaling suppression by retinal pericyte conditioned medium prevents retinal endothelial cell proliferation. 1549 72

Focal adhesion kinase (FAK) is a 125 kDa protein tyrosine kinase (PTK) associated with focal adhesion in many cells, which plays a major role in the integrity of cytoskeletal structure. Reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of signal transduction process. We found that low dose H2O2 induced increased FAK production in pulmonary microvascular endothelial cells, which could be blocked by cycloheximide (CHX), a protein synthesis inhibitor. Pulmonary endothelial cells were cultured on DMEM medium till 100% confluent. H2O2 was added at 100 uM for 30 min. The cells were collected and lysed, then immuno-blotted with anti-FAK antibody. After 30 min treatment, we found a 30%+/-6% (N=5) increase of FAK in H2O2 treated endothelial cells. This increase could be blocked by pretreatment of cells with CHX at 5 ug/ml for 60 min. In both groups, increased phosphorylation of ERK was observed. Immuno-fluorescence revealed increased staining of FAK in the peri-nuclear region of the H2O2 treated endothelial cells. These findings suggest that H2O2 activated MAP kinase pathway leading to increased FAK production at the protein level. FAK is a 125 kDa PTK associated with focal adhesion in many cells, and it plays a major role in the integrity of cytoskeletal structure. FAK is discretely localized to focal adhesions via its C-terminal focal adhesion-targeting (FAT) sequence. FAK is regulated by integrin-dependent cell adhesion and can control tyrosine phosphorylation of downstream substrates, like paxillin. The reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of the signal transduction process. Although the signaling pathways leading to hydrogen peroxide induced endothelial monolayer permeability remain ambiguous, cytoskeletal proteins are known to be essential for maintaining endothelial integrity and regulating solute flux through the monolayer. Recent evidence has shown that H2O2 stimulates cytoskeleton reorganization, cell growth/proliferation, and DNA synthesis in various cells. In our previous study, we found a significantly increased amount of FAK in endothelial cells treated with low doses of H2O2. Mitogen-activated protein (MAP) kinases are a group of 30- to 110-kDa serine/threonine kinases. MAPKs belong to the group of kinases that are rapidly activated in response to growth factor stimulation. This family of MAPKs includes ERK, and ERK2. The activated MAPK can translocate to the nucleus where it can regulate transcription factors. Activation of p44 and p42 extracellular signal-regulated protein kinases (ERK1 and ERK2) is an important step in the cascade leading to cell growth and proliferation. In order to determine the mechanism of increased FAK production, we investigated the relationship of FAK production and ERK activation.
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PMID:Reactive oxygen species increased focal adhesion kinase production in pulmonary microvascular endothelial cells. 1563 12

Osteopontin (OPN) is a secreted extracellular phosphoprotein involved in diverse biologic functions, including inflammation, cell migration, and antiapoptotic processes. Here we investigate the neuroprotective potential of OPN to reduce cell death using both in vitro and in vivo models of ischemia. We show that incubation of cortical neuron cultures with OPN protects against cell death from oxygen and glucose deprivation. The effect of OPN depends on the Arg-Gly-Asp (RGD)-containing motif as the protective effect of OPN in vitro was blocked by an RGD-containing hexapeptide, which prevents integrin receptors binding to their ligands. Osteopontin treatment of cortical neuron cultures caused an increase in Akt and p42/p44 MAPK phosphorylation, which is consistent with OPN-inducing neuroprotection via the activation of these protein kinases. Indeed, the protective effect of OPN was reduced by inhibiting the activation of Akt and p42/p44 MAPK using LY294002 and U0126, respectively. The protective effect of OPN was also blocked by the protein synthesis inhibitor cycloheximide, suggesting that the neuroprotective effect of OPN required new protein synthesis. Finally, intracerebral ventricular administration of OPN caused a marked reduction in infarct size after transient middle cerebral artery occlusion in a murine stroke model. These data suggest that OPN is a potent neuroprotectant against ischemic injury.
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PMID:Neuroprotection by osteopontin in stroke. 1567 24

We investigated the potential role of atorvastatin, given at reperfusion, to improve survival of the ischemic/reperfused myocardium by activation of p44/42 MAPK and p38 MAPK with its downstream effector, HSP27. We have previously shown that atorvastatin attenuates lethal reperfusion-induced injury via activation of the phosphatidyl inositol 3-kinase (PI3K) prosurvival signaling pathway. In this study we hypothesize that other prosurvival kinases may also be implicated in this protection. Langendorff-perfused mouse hearts were subjected to 35 minutes of global ischemia followed by 30 minutes of reperfusion, and either infarct size or the levels of phosphorylated AKT, p44/42 MAPK, p38 MAPK, and HSP27 were analyzed. Atorvastatin was administered during reperfusion only. We used wortmannin to block PI3K/AKT, U0126 to block p44/42 MAPK, and SB203580 to prevent the phosphorylation of p38 MAPK and HSP27. Atorvastatin significantly reduced infarct size (32.96 +/- 3.4% versus 51.27 +/- 2.79% in controls, P < 0.05). This protection was abrogated by wortmannin (48.38 +/- 4.28%), U0126 (52.58 +/- 7.58), and SB203580 (49.37 +/- 4.16%). Western blot analysis confirmed significant phosphorylation of AKT, p44/42 MAPK, p38 MAPK, and HSP27 following administration of atorvastatin during reperfusion and abrogation of the respective phosphorylation in the presence of their specific inhibitors. Atorvastatin given at reperfusion attenuates lethal reperfusion-induced injury by the phosphorylation of multiple prosurvival pathways involving not only PI3K/AKT but also p44/42 MAPK, p38 MAPK, and HSP27.
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PMID:Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling. 1572 50

Tissue damage after ischemia and reperfusion (I/R) is largely caused by the sequelae of neutrophil infiltration. This inflammatory process can be initiated as the result of stroke, coronary ischemia, trauma, and other related conditions. The infiltration of neutrophils is facilitated by the expression of adhesion molecules on the surface of endothelial cells. Particularly important are the selectin family of adhesion molecules at the onset of neutrophil-mediated injury. The aim of this study was to determine the role of selectin inhibition in the modulation of chemokine expression and Akt/MAPK signaling after liver I/R. In addition, we evaluated the optimal dose and time of administration of a small molecule selectin inhibitor, TBC-1269. Mice subjected to 90 min of partial (70-80%) hepatic ischemia followed by 3 h of reperfusion were divided into 15 groups (n = 4/group); sham, ischemic control, and 10, 20, and 40 mg/kg dose groups for the antiselectin molecule were studied at 3 times of drug administration: 1 h before reperfusion (but after ischemia), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured after 3 h of reperfusion included liver function tests (ALT and AST), histopathology, and tissue myeloperoxidase (MPO). Chemokine expression (MIP-1alpha, MIP-1beta, MIP-2 and KC), Akt, MAPK (p44/p42), and RSK expressions were also measured in liver tissue by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. It was demonstrated that the small molecule multi-selectin inhibitor (TBC-1269) offered the most significant protection for the ischemic liver when given at 40 mg/kg at the time ofreperfusion. AST significantly differed between the control group and the group receiving 40 mg/kg at the time of reperfusion (p = .01). MPO levels in the liver tissue of the ischemic controls were significantly increased when compared to the levels of this enzyme in the TBC-1269 group at 40 mg/kg. Histological examination reflected the same results, with a significant difference (p = .02) between these same two groups. The chemokine profile also showed that the same treatment group had a downregulation of MIP-lalpha, MIP-1beta, MIP-2, and KC, as well as a lower expression of Akt, MAPK(p44/42), and RSK when compared to the control group. Thus, we demonstrated that the small molecule selectin inhibitor, TBC-1269, offered significant functional and structural protection of the ischemic liver when given at 40 mg/kg at the time of reperfusion. Lower doses and different times of administration did not show as prominent a drug effect. This selectin inhibition modulated the expression of Akt, MAPK (p44/42), and RSK, as well as MIP-1alpha, MIP-1beta, MIP-2, and KC chemokines. These alterations in cellular signaling and chemokine expression represent potential mechanisms or pathways of inflammatory response in I/R.
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PMID:Selectin inhibition modulates Akt/MAPK signaling and chemokine expression after liver ischemia-reperfusion. 1576 97

Ifenprodil, a non-competitive NMDA-receptor antagonist, has been shown to exhibit marked cytoprotective activities in animal models for focal ischemia and Parkinson's disease. To test the hypothesis that the cytoprotective effect is due to the release of neurotrophic factors (NTFs), we examined the effects of ifenprodil on the NTF contents in mouse astrocyte cultures. The results revealed that ifenprodil strongly enhanced the production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in these cultures. The ifenprodil-induced NGF secretion was found to be partially mediated by the activation of protein kinase C (PKC) and p42/p44 mitogen-activated protein (MAP) kinase cascade pathways. These findings suggest that the cytoprotective effects of ifenprodil are probably attributed to enhanced secretion of these NTFs from astrocytes.
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PMID:Production of NGF, BDNF and GDNF in mouse astrocyte cultures is strongly enhanced by a cerebral vasodilator, ifenprodil. 1584 60

In vivo, pathological conditions such as ischemia and ischemia/reperfusion are known to damage the blood-brain barrier (BBB) leading to the development of vasogenic brain edema. Using an in vitro model of the BBB, consisting of brain-derived microvascular endothelial cells (BMEC), it was demonstrated that hypoxia-induced paracellular permeability was strongly aggravated by reoxygenation (H/R), which was prevented by catalase suggesting that H2O2 is the main mediator of the reoxygenation effect. Therefore, mechanisms leading to H2O2-induced hyperpermeability were investigated. N-acetylcysteine and suramin and furthermore usage of a G protein antagonist inhibited H202 effects suggesting that activation of cell surface receptors coupled to G proteins may mediate signal initiation by H2O2. Further, H2O2 activated phospholipase C (PLC) and increased the intracellular Ca2+ release because U73122, TMB-8, and the calmodulin antagonist W7 inhibited H2O2-induced hyperpermeability. H2O2 did not activate protein kinase C (PKC), nitric-oxide synthase (NOS), and phosphatidyl-inositol-3 kinase (PI3-K/Akt). Inhibition of the extracellular signal-regulated kinase (ERK1/ERK2 or p44/42 MAPK), but not of the p38 and of the c-jun NH2-terminal kinase (JNK), inhibited hyperpermeability by H2O2 and H/R completely. Corresponding to H2O2- and H/R-induced permeability changes the phosphorylation of the p44/42 MAP kinase was inhibited by the specific MAP kinase inhibitor PD98059 and by TMB-8 and W7. Paracellular permeability changes by H2O2 correlated to changes of the localization of the tight junction (TJ) proteins occludin, zonula occludens 1 (ZO-1), and zonula occludens 2 (ZO-2) which were prevented by blocking the p44/p42 MAP kinase activation. Results suggest that H2O2 is the main inducer of H/R-induced permeability changes. The hyperpermeability is caused by activation of PLC via receptor activation leading to the intracellular release of Ca2+ followed by activation of the p44/42 MAP kinase and paracellular permeability changes mediated by changes of the localization of TJ proteins.
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PMID:H2O2 induces paracellular permeability of porcine brain-derived microvascular endothelial cells by activation of the p44/42 MAP kinase pathway. 1610 12

Prostanoids in the central nervous system define an important linkage between blood pressure and hormonal responses to hypotension/ischemia. Prostaglandin endoperoxide synthase (PGHS)-2, the inducible isoform of this enzyme, is induced by cerebral hypoperfusion/ischemia. To investigate the mechanism of the PGHS-2 gene expression in response to cerebral hypoperfusion/ischemia in neurons, we used a cell culture model (human SK-N-AS cells) to mimic the oxygen and glucose deprivation (OGD) that usually results from ischemia. Whereas OGD stimulated robust increases in PGHS-2 mRNA abundance, neither oxygen nor glucose deprivation alone was effective. Our data demonstrated that induction of both PGHS-2 mRNA and protein reached peak levels ( approximately 10 fold) after 6 h OGD. This was partially blocked by the inhibition of mitogen-activated protein kinase (MAPK) p38, and was almost completely blocked by the inhibition of extracellular signal-related kinases 1/2 (ERK1/2 or p44/42), another MAPK. These results indicate that PGHS-2 gene expression is induced by oxygen and glucose deprivation synergistically in neurons, and this induction is mediated by one or more members of the MAPK family.
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PMID:Neuronal prostaglandin endoperoxide synthase 2 responses to oxygen and glucose deprivation are mediated by mitogen-activated protein kinase ERK1/2. 1618 70

Mitogen-activated protein kinases (MAPK) play a pivotal role in ischemia reperfusion injuries of heart and liver, but the activation pattern of MAPKs in the early phase of different size liver isografts remains unclear. The experiment is designed to investigate the activation pattern and role of MAPKs in isografts of the rat with different size liver transplantation. The animal models of different size graft liver transplantation (whole graft, 50% size, or 30% size, respectively) were established and the sham operation group served as a control. The recipients were sacrificed at 0.5-, 2-, 6-, and 24-hour time points after transplantation to harvest the graft specimens and blood samples. The serum aspartate amino transferase (AST), alanine amino transferase (ALT) and tumor necrosis factor-alpha (TNF-alpha) levels, and histological findings were evaluated. The expressions of the total and phosphorylated p46/p54 JNKs, p38 MAPK, and p42/p44 ERKs were detected by Western blot. The serum ALT and AST levels increased significantly at the 0.5-hour time point and maintained high with the peak levels at the 6-hour time point after liver transplantation. The different sizes of liver isografts did not change the expressions of total p46/p54JNKs, p38MAPK, and p42/p44 ERKs. While the expressions of phosphorylated p46/p54JNKs, p38 MAPK, and p42/p44 ERKs were either negative or mildly up-regulated in the sham operation group, they were significantly activated in the transplanted liver at the 0.5-hour time point, especially in the 30% size liver transplantation group. In conclusion, the activation of three MAPKs in liver isografts correlates with graft size and the JNK and p38 MAPK are responsible for the graft injury while the ERK signal pathway maybe participate in the regulation of cell growth and differentiation after small-for-size liver transplantation.
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PMID:Activation pattern of mitogen-activated protein kinases in early phase of different size liver isografts in rats. 1631 91


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