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)

Previous studies have shown that ischemia and reperfusion are potent stimuli for eliciting cardiomyocyte apoptosis, and that polymorphonuclear leukocytes (PMNs) are involved in the development of myocardial injury induced by ischemia and reperfusion. The present study examined whether PMN could directly induce cardiomyocyte apoptosis and, if so, it possible signal transduction pathways. In addition, we also investigated the effects of carvedilol, a potent antioxidant, on PMN-induced apoptosis. Cultured primary neonatal rat cardiomyocytes were exposed to PAF-activated PMNs at concentrations of 10(5), 3 x 10(5) and 10(6) cells/well for 48 h. Multiple detecting techniques, including electron microscopy, DNA gel electrophoresis. TUNEL assay and flow cytometry were used to identify myocyte apoptosis. All of these techniques demonstrated that activated PMNs directly induced cardiomyocyte apoptosis in a concentration-dependent manner, while unactivated PMNs showed no such effect. Activated PMN-induced apoptosis was partially inhibited by SB203580, a specific inhibitor of the p38-MAPK signaling system. Carvedilol (at a dose range of 1-10 mumol/l) significantly prevented activated PMN-induced cardiomyocyte apoptosis. These results suggest that PMNs, when activated, directly induce cardiomyocyte apoptosis and that the p38-MAPK signaling pathway might be involved in this process. Carvedilol may prevent PMN-induced apoptosis possibly because of its antioxidant properties.
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PMID:Activated polymorphonuclear leukocytes induce cardiomyocyte apoptosis and the protective effects of carvedilol. 1242 28

The Na(+)/Ca(2+) exchanger (NCX1) is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. Following pressure overload, activation of MAPKs coincides with the kinetics of NCX1 gene upregulation in adult cardiocytes. Using adenoviral gene delivery, we begin to identify the molecular pathways responsible for upregulation of the exchanger gene. Inhibition of ERK with the MEK inhibitor UO126, the ERK protein phosphatase MKP-3, inhibited ERK activation, but only inhibited alpha-adrenergic-induced NCX1 upregulation by 30%. Overexpression of DN-JNK lowered basal NCX1 expression. Overexpression of activated MKK-3 was sufficient for alpha-adrenergic-stimulated upregulation of the reporter gene. Together, this data indicates that (1) JNK mediates basal cardiac expression of the NCX1 gene, (2) ERK and p38 play a role in alpha-adrenergic-stimulated NCX1 upregulation, and (3) p38 activation alone is sufficient for NCX1 upregulation.
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PMID:Pathways regulating Na+/Ca2+ exchanger expression in the heart. 1250 66

Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes connecting cell-surface receptors to critical regulatory targets within cells. The three major MAPK cascades are known, the extracellular signal-regulated protein kinase (ERK) cascade, c-Jun amino-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) cascade and p38-MAPK cascade. This paper is focused on characterization of these MAPK cascades in terms of their distribution and biological role in some pathological processes (apoptosis, hypertrophy) with a special orientation on the role of MAPKs in cardiovascular system during ischemia/reperfusion.
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PMID:Mitogen-activated protein kinases and their role in regulation of cellular processes. 1253 49

Atrial natriuretic peptide (ANP) reduces ischemia and/or reperfusion damage in several organs, but the mechanisms involved are largely unknown. We used freshly isolated rat hepatocytes to investigate the mechanisms by which ANP enhances hepatocyte resistance to hypoxia. The addition of ANP (1 micromol/L) reduced the killing of hypoxic hepatocytes by interfering with intracellular Na(+) accumulation without ameliorating adenosine triphosphate (ATP) depletion and pH decrease caused by hypoxia. The effects of ANP were mimicked by 8-bromo-guanosine 3', 5'-cyclic monophosphate (cGMP) and were associated with the activation of cGMP-dependent kinase (cGK), suggesting the involvement of guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A/B ANP receptors. However, stimulating NPR-C receptor with des-(Gln(18), Ser(19),Gly(20),Leu(21),Gly(22))-ANP fragment 4-23 amide (C-ANP) also increased hepatocyte tolerance to hypoxia. C-ANP protection did not involve cGK activation but was instead linked to the stimulation of protein kinase C (PKC)-delta through G(i) protein- and phospholipase C-mediated signals. PKC-delta activation was also observed in hepatocytes receiving ANP. The inhibition of phospholipase C or PKC by U73122 and chelerythrine, respectively, significantly reduced ANP cytoprotection, indicating that ANP interaction with NPR-C receptors also contributed to cytoprotection. In ANP-treated hepatocytes, the stimulation of both cGK and PKC-delta was coupled with dual phosphorylation of p38 mitogen-activated protein kinase (MAPK). The p38 MAPK inhibitor SB203580 abolished ANP protection by reverting p38 MAPK-mediated regulation of Na(+) influx by the Na(+)/H(+) exchanger. In conclusion, ANP recruits 2 independent signal pathways, one mediated by cGMP and cGK and the other associated with G(i) proteins, phospholipase C, and PKC-delta. Both cGK and PKC-delta further transduce ANP signals to p38 MAPK that, by maintaining Na(+) homeostasis, are responsible for ANP protection against hypoxic injury.
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PMID:Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide. 1254 Jul 77

Ischemic preconditioning (IP) triggers protection of the liver from prolonged subsequent ischemia. However, the underlying protective mechanisms are largely unknown. We investigated whether and how IP protects the liver against reperfusion injury caused by Kupffer cell (KC)-derived oxidants. IP before 90 minutes of warm ischemia of rat livers in vivo significantly reduced serum alanine aminotransferase (AST) levels and leukocyte adherence to sinusoids and postsinusoidal venules during reperfusion. This protective effect was mimicked by postischemic intravenous infusion of glutathione (GSH), an antioxidative strategy against KC-derived H(2)O(2). Interestingly, no additional protection was achieved by infusion of GSH to preconditioned animals. These findings and several additional experiments strongly suggest IP mediated antioxidative effects: IP prevented oxidant cell injury in isolated perfused rat livers after selective KC activation by zymosan. Moreover, IP prevented cell injury and pertubations of the intracellular GSH/GSSG redox system caused by direct infusion of H(2)O(2) (0.5 mmol/L). IP-mediated resistance against H(2)O(2) could neither be blocked by the adenosine A2a antagonist DMPX nor mimicked by A2a agonist CGS21680. In contrast, H(2)O(2) resistance was abolished by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, but induced when p38 MAPK was directly activated by anisomycin. In conclusion, we propose a novel concept of hepatoprotection by IP: protection of liver cells by enhancing their resistance against KC-derived H(2)O(2). Activation of p38 MAPK and preservation of the intracellular GSH/oxidized glutathione (GSSG) redox system, but not adenosine A2a receptor stimulation, seems to be pivotal for the development of H(2)O(2) resistance in preconditioned livers.
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PMID:Induction of cellular resistance against Kupffer cell-derived oxidant stress: a novel concept of hepatoprotection by ischemic preconditioning. 1254 Jul 78

We tested the response of stress-activated mitogen-activated protein kinases (MAPKs) - p38 MAPK and c-JUN NH2-terminal kinase (JNK) - following hypoxia-ischemia (H-I) induced by unilateral carotid artery ligation and hypoxia (8% O2 and 92% N2) for 2.5 h in postnatal-day-7 rats. Phosphorylation of p38 MAPK increased in the hippocampus and cortex immediately following H-I and returned to a basal level 6 h later. In contrast to p38 MAPK, phosphorylation of JNK decreased in the hippocampus and cortex immediately following H-I. Intracerebroventricular administration of two different p38 MAPK inhibitors prior to H-I significantly protected the neonatal brain from H-I injury. Interestingly, p38 MAPK inhibitors did not attenuate caspase-3 activation 24 h after H-I. Thus, these data suggest that p38 MAPKs contribute to the rapid, early component of brain injury following neonatal H-I.
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PMID:Evidence that p38 mitogen-activated protein kinase contributes to neonatal hypoxic-ischemic brain injury. 1264 Jan 79

Focal ischemia induced by middle cerebral artery occlusion (MCAO) to adult rats results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Upstream from the cell death promoters and executioners are several kinases that, once activated by phosphorylation, may activate several transcription factor substrates involved in cell death and cell survival. In the present study we examined, by immunohistochemistry, the expression of phosphorylated (active) mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK), stress-activated protein kinase (SAPK), c-Jun N-terminal kinase (JNK) and p-38 kinase at early stages (1-4 h) following 1 h of MCAO in the rat. The expression of phosphorylation-dependent, active transcription substrates of these kinases, including cyclic AMP-responsive element-binding protein (CREB) Alk-1, ATF-2, c-Myc and c-Jun was examined at early stages following reperfusion. Increased nuclear phosphorylated SAPK/JNK (SAPK/JNK-P) and c-Jun-PSer63, and reduced CREB-P, occurred in the infarct core at 1 h following reperfusion, suggesting increased phosphorylated SAPK/JNK and c-JunSer63, together with decreased phospho-CREB associated with cell death in the infarct core. However, increased cytoplasmic expression of MAPK/ERK-P, SAPK/JNK-P, p38-P, CREB-P, Elk-1-P, c-Myc-P, ATF-2-P and c-Jun-P occurred in the region bordering the infarct core (penumbra) at 4 h following reperfusion. This indicates that different signals converge in the cytoplasm of neurons located at the borders of the infarct at 4 h following reperfusion, revealing the struggle of death promoters and life facilitators at the penumbra. Whether phosphorylated kinases and specific substrates participate in promoting cell death or survival in the penumbra probably depends on additional factors and on the interaction with other proteins.
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PMID:Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. 1267 42

Multiple stress proteins are recruited in response to stress in living cells. There are limited reports in the literature analyzing multiple stress protein shifts and their functional consequences on stress response. Using two-dimensional electrophoresis we have analyzed shifts in stress protein profiles in response to energy deprivation as a model of ischemic injury to kidneys. A group of chaperones and stress-induced mitogen activated protein (MAP) kinases were analyzed. In addition to examining stress protein induction and phosphorylation we have also examined the mechanism of cytoprotection by heat shock protein 70 (Hsp70). Our results show that, of the different stress proteins examined, only binding protein (BiP) and Hsp70 were significantly induced upon energy deprivation. Other stress proteins, including Hsp27, calnexin, Hsp90 and ERp57 showed alterations in their phosphorylation profiles. Three different MAP kinases, namely p38, extracellular signal regulated kisase and c-jun N-terminal kinase (JNK) were activated in response to energy deprivation. While JNK activation was linked to apoptosis, activated-p38 was involved in phosphorylation of Hsp27. Study of inhibitors of Hsp70 induction or pre-induction of Hsp70 indicated that induced Hsp70 was involved in the suppression of JNK activation thereby inhibiting apoptotic cell death. Our results provide important insights into the flux in stress protein profiles in response to simulated ischemia and highlight the antiapoptotic, cytoprotective mechanism of Hsp70 action.
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PMID:Stress protein flux during recovery from simulated ischemia: induced heat shock protein 70 confers cytoprotection by suppressing JNK activation and inhibiting apoptotic cell death. 1268 18

Carbon monoxide is protective in ischemia-reperfusion organ injury, but the precise mechanisms remain elusive. We have recently shown that low levels of exogenous carbon monoxide (CO) utilize p38 MAPK and attenuate caspase 3 activity to exert an antiapoptotic effect during lung ischemia-reperfusion injury. Our current data demonstrate that CO activates the p38alpha MAPK isoform and the upstream MAPK kinase MKK3 to modulate Fas/Fas ligand expression; caspases 3, 8, and 9; mitochondrial cytochrome c release; Bcl-2 proteins; and poly(ADP-ribose) polymerase cleavage. We correlate our in vitro findings with in vivo studies using MKK3-deficient and Fas-deficient mice. Taken together, our data are the first to demonstrate that CO has an antiapoptotic effect by inhibiting Fas/Fas ligand, caspases, proapoptotic Bcl-2 proteins, and cytochrome c release via the MKK3/p38alpha MAPK pathway.
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PMID:Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. 1269 Jan

The ischemic activation of p38alpha mitogen-activated protein kinase (p38alpha-MAPK) is thought to contribute to myocardial injury. Under other circumstances, activation is through dual phosphorylation by MAPK kinase 3 (MKK3). Therefore, the mkk3-/- murine heart should be protected during ischemia. In retrogradely perfused mkk3-/- and mkk3+/+ mouse hearts subjected to 30 minutes of global ischemia and 120 minutes of reperfusion, infarction/risk volume was similar (50+/-5 versus 51+/-4, P=0.93, respectively), as was intraischemic p38-MAPK phosphorylation (10 minutes ischemia as percent basal, 608+/-224 versus 384+/-104, P=0.43, respectively). This occurred despite undetectable activation of MKK3/6 in mkk3-/- hearts. However, tumor necrosis factor (TNF)-induced p38-MAPK phosphorylation was markedly diminished in mkk3-/- vs mkk3+/+ hearts (percent basal, 127+/-23 versus 540+/-267, respectively, P=0.04), suggesting an MKK-independent activation mechanism by ischemia. Hence, we examined p38-MAPK activation by TAB1-associated autophosphorylation. In wild-type mice and mkk3-/- mice, the p38-MAPK catalytic site inhibitor SB203580 (1 micromol/L) diminished phosphorylation during ischemia versus control (10 minutes ischemia as percent basal, 143+/-2 versus 436+/-96, P=0.003, and 122+/-25 versus 623+/-176, P=0.05, respectively) and reduced infarction volume (infarction/risk volume, 57+/-5 versus 36+/-3, P<0.001, and 50+/-5 versus 29+/-3, P=0.003, respectively) but did not alter TNF-induced activation, although in homogenates of ischemic hearts but not TNF-exposed hearts, p38-MAPK was associated with TAB1. Furthermore, adenovirally expressed wild-type and drug-resistant p38alpha-MAPK, lacking the SB203580 binding site, was phosphorylated when H9c2 myoblasts were subjected to simulated ischemia. However, SB203580 (1 micromol/L) did not prevent the phosphorylation of resistant p38alpha-MAPK. These findings suggest the ischemic activation of p38-MAPK contributing to myocardial injury is by TAB1-associated autophosphorylation.
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PMID:Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. 1282 18


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