UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p38 mitogen-activated protein kinase (MAPK) is known to be activated after exposure to endotoxin, osmotic and environmental stress, and, most recently, during ischemia/reperfusion. We investigated whether ischemic preconditioning also causes phosphorylation of the activation sites on p38 MAPK. Three groups of isolated rabbit hearts were studied. Control hearts experienced 30 min of ischemia only. The second group was preconditioned with 5 min of global ischemia and 10 min of reperfusion. Group 3 was also ischemically preconditioned, but in the presence of 100 microM 8-(p-sulfophenyl)theophylline (SPT). Transmural left ventricular biopsies were taken before and during the long ischemic period. Western blot analysis with either p38 MAPK or phospho-specific p38 MAPK (Tyr-182) antibodies showed a decreased phosphorylation during ischemia in non-preconditioned hearts, but phosphorylation was enhanced several fold after 10 and 20 min of ischemia in preconditioned hearts. Furthermore, when protection from ischemic preconditioning was blocked by SPT, increased phosphorylation of p38 MAPK during ischemia was not present. Therefore the phosphorylation of p38 MAPK at tyrosine 182, which is required for the kinase's activation, occurred during ischemia only when protection from preconditioning was evident. In a second study, changes in osmotic fragility were measured during simulated ischemia in rabbit cardiomyocytes. Reduced fragility in ischemically preconditioned myocytes could be completely abolished by the specific p38 MAPK inhibitor SB-203580. In contrast, anisomycin, an activator of p38 MAPK and JUN kinase pathways, was found to be as protective as ischemic preconditioning. We conclude that p38 MAPK phosphorylation correlates with preconditioning's protection, and that its activation may be an important step in the signal transduction cascade of ischemic preconditioning.
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PMID:Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. 929 62

Myocardial infarction results in focal areas of ischemia, hypoxia, necrosis, and decreased contractile function. To compensate for loss of contractile function, remaining viable myocytes undergo hypertrophic growth. Prostaglandin F2alpha (PGF2alpha), which is released from cells of the myocardium during periods of stress such as hypoxia or ischemia/reperfusion, has recently been shown to stimulate hypertrophic growth in neonatal rat ventricular myocytes. In the present study, we determine which growth-related intracellular pathways are required for PGF2alpha to induce morphological and genetic features characteristic of the hypertrophic phenotype. In cardiomyocytes, PGF2alpha increases the hydrolysis of inositol phosphates and induces the translocation of protein kinase C epsilon to the myocyte membrane, consistent with PGF2alpha receptor coupling to Gq. PGF2alpha also activates the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase pathways. Surprisingly, studies using pharmacological inhibitors and transfection of dominant-interfering proteins demonstrate that PGF2alpha-induced myocyte hypertrophy occurs independent of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF2alpha stimulates protein tyrosine phosphorylation and activates c-Jun NH2-terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF2alpha.
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PMID:Tyrosine kinase and c-Jun NH2-terminal kinase mediate hypertrophic responses to prostaglandin F2alpha in cultured neonatal rat ventricular myocytes. 968 56

Cellular ischemia results in activation of a number of kinases, including p38 mitogen-activated protein kinase (MAPK); however, it is not yet clear whether p38 MAPK activation plays a role in cellular damage or is part of a protective response against ischemia. We have developed a model to study ischemia in cultured neonatal rat cardiac myocytes. In this model, two distinct phases of p38 MAPK activation were observed during ischemia. The first phase began within 10 min and lasted less than 1 h, and the second began after 2 h and lasted throughout the ischemic period. Similar to previous studies using in vivo models, the nonspecific activator of p38 MAPK and c-Jun NH2-terminal kinase, anisomycin, protected cardiac myocytes from ischemic injury, decreasing the release of cytosolic lactate dehydrogenase by approximately 25%. We demonstrated, however, that a selective inhibitor of p38 MAPK, SB 203580, also protected cardiac myocytes against extended ischemia in a dose-dependent manner. The protective effect was seen even when the inhibitor was present during only the second, sustained phase of p38 MAPK activation. We found that ischemia induced apoptosis in neonatal rat cardiac myocytes and that SB 203580 reduced activation of caspase-3, a key event in apoptosis. These results suggest that p38 MAPK induces apoptosis during ischemia in cardiac myocytes and that selective inhibition of p38 MAPK could be developed as a potential therapy for ischemic heart disease.
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PMID:An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. 1003 15

Recent evidence has implicated proinflammatory mediators such as TNF-alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Both cardiopulmonary bypass and renal ischemia-reperfusion injury induce a cascade of events leading to cellular damage and organ dysfunction. Tumor necrosis factor (TNF), a potent proinflammatory cytokine, is released from both the heart and the kidney in response to ischemia and reperfusion. TNF released during cardiopulmonary bypass induces glomerular fibrin deposition, cellular infiltration, and vasoconstriction, leading to a reduction in glomerular filtration rate (GFR). The signaling cascade through which renal ischemia-reperfusion induces TNF production is beginning to be elucidated. Oxidants released following reperfusion activate p38 mitogen-activated protein kinase (p38 MAP kinase) and the TNF transcription factor, NFkappaB, leading to subsequent TNF synthesis. In a positive feedback, proinflammatory fashion, binding of TNF to specific TNF membrane receptors can reactivate NFkappaB. This provides a mechanism by which TNF can upregulate its own expression as well as facilitate the expression of other genes pivotal to the inflammatory response. Following its production and release, TNF results in both renal and myocardial apoptosis and dysfunction. An understanding of these mechanisms may allow the adjuvant use of anti-TNF therapeutic strategies in the treatment of renal injury. The purposes of this review are: (1) to evaluate the evidence which indicates that TNF is produced by the heart following cardiopulmonary bypass; (2) to examine the effect of TNF on myocardial performance; (3) to outline the mechanisms by which the kidney produces significant TNF in response to ischemia and reperfusion; (5) to investigate the role of TNF in renal ischemia-reperfusion injury, (6) to describe the mechanisms of TNF-induced renal cell apoptosis, and (7) to suggest potential anti-TNF strategies designed to reduce renal insufficiency following cardiac surgery.
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PMID:Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome. 1042 18

A conscious rabbit model was used to study the effect of ischemic preconditioning (PC) on stress-activated kinases [c-Jun NH(2)-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (MAPK)] in an environment free of surgical trauma and attending external stress. Ischemic PC (6 cycles of 4-min ischemia/4-min reperfusion) induced significant activation of protein kinase C (PKC)-epsilon in the particulate fraction, which was associated with activation of p46 JNK in the nuclear fraction and p54 JNK in the cytosolic fraction; all of these changes were completely abolised by the PKC inhibitor chelerythrine. Selective enhancement of PKC-epsilon activity in adult rabbit cardiac myocytes resulted in enhanced activity of p46/p54 JNKs, providing direct in vitro evidence that PKC-epsilon is coupled to both kinases. Studies in rabbits showed that the activation of p46 JNK occurred during ischemia, whereas that of p54 JNK occurred after reperfusion. A single 4-min period of ischemia induced a robust activation of the p38 MAPK cascade, which, however, was attenuated after 5 min of reperfusion and disappeared after six cycles of 4-min ischemia/reperfusion. Overexpression of PKC-epsilon in cardiac myocytes failed to increase the p38 MAPK activity. These results demonstrate that ischemic PC activates p46 and p54 JNKs via a PKC-epsilon-dependent signaling pathway and that there are important differences between p46 and p54 JNKs with respect to the subcellular compartment (cytosolic vs. nuclear) and the mechanism (ischemia vs. reperfusion) of their activation after ischemic PC.
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PMID:PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. 1056 30

Recent studies suggest that p38 mitogen-activated protein kinase (MAPK) may be involved in ischemic preconditioning (PC). To further test this possibility, the regulation of MAPK-activated protein kinase 2 (MAPKAPK2), a kinase immediately downstream from p38 MAPK, and the activity of c-Jun NH(2)-terminal kinase (JNK), a second MAPK, were examined in preconditioned hearts. Isolated, perfused rabbit hearts were subjected to 20 to 30 minutes of global ischemia. Ventricular biopsies before treatment and after 20 minutes of ischemia were homogenized, and the activities of MAPKAPK2 and JNK were evaluated. For the MAPKAPK2 experiments, 7 groups were studied, as follows: control hearts; preconditioned hearts; hearts treated with 500 nmol/L R(-) N(6)-(2-phenylisopropyl) adenosine (PIA), an A(1)-adenosine receptor agonist; preconditioned hearts pretreated with 100 micromol/L 8-(p-sulfophenyl) theophylline (SPT), an adenosine receptor antagonist; preconditioned hearts also treated with SB 203580, a potent inhibitor of p38 MAPK activation; hearts treated with 50 ng/mL anisomycin (a p38 MAPK/JNK activator); and hearts treated with both anisomycin (50 ng/mL) and the tyrosine kinase inhibitor genistein (50 micromol/L). MAPKAPK2 activity was not altered in control hearts after 20 minutes of global ischemia. By contrast, there was a 3.8-fold increase in activity during ischemia in preconditioned hearts. Activation of MAPKAPK2 in preconditioned hearts was blocked by both SPT and SB 203580. MAPKAPK2 activity during ischemia increased 3.5-fold and 3.3-fold in hearts pretreated with PIA or anisomycin, respectively. MAPKAPK2 activation during ischemia in hearts pretreated with anisomycin was blocked by genistein. In separate hearts, anisomycin mimicked the anti-infarct effect of PC, and that protection was abolished by genistein. JNK activity was measured in control and preconditioned hearts. There was a comparable, modest decline in activity during 30 minutes of global ischemia in both groups. As a positive control, a third group of hearts was treated with anisomycin before global ischemia, and in these, JNK activity increased by 290% above baseline. These results confirm that the p38 MAPK/MAPKAPK2 pathway is activated during ischemia only if the heart is in a preconditioned state. These data further support p38 MAPK as an important signaling component in ischemic PC.
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PMID:Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. 1066 9

alpha-Phenyl-N-tert-butylnitrone (PBN), a spin trap, is known as a protective agent against delayed-neuronal death after ischemia-reperfusion. To investigate this neuroprotective effect of PBN, we examined the effect of PBN on the mitogen-activated protein kinase (MAPK) signaling pathway and the expression of heat shock proteins (HSPs) in the gerbil hippocampus following transient (5 min) ischemia. Immunoblot analysis revealed that intraperitoneal (i. p.) injection of PBN (200 mg/kg) enhanced the activation of extracellular-response kinase (ERK) and suppressed the activation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 mitogen-activated protein kinase (p38) at 6 h after ischemia. Elevated levels of HSP27 and HSP70 were seen at the same period. These data suggest that PBN protects against delayed-neuronal death not only by its inherent radical-trapping activity but also by regulating the MAPK pathway and up-regulating HSPs.
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PMID:Neuroprotective effect of alpha-phenyl-N-tert-butylnitrone in gerbil hippocampus is mediated by the mitogen-activated protein kinase pathway and heat shock proteins. 1071 91

Transient adenosine A(1) receptor (A(1)R) activation in rabbits induces delayed preconditioning against myocardial infarction 24 to 72 hours later. The cellular mechanisms downstream of A(1)R mediating this delayed cardioprotection have not been elucidated. This study examined the role of protein kinase C (PKC) and tyrosine kinases (TKs) in the signaling cascade mediating A(1)R-induced late preconditioning in rabbits. The small heat shock protein Hsp27 has been shown to confer cytoskeletal protection when in the phosphorylated state. We therefore also evaluated the potential role of the p38 mitogen-activated protein kinase (p38 MAPK) and Hsp27 as distal mediators of A(1)R-induced delayed preconditioning. Pharmacological preconditioning of rabbits with the selective A(1) agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 100 microgram/kg) significantly reduced myocardial infarct size compared with control animals, after 30-minute regional ischemia/2-hour reperfusion in vivo 24 hours later (23.7+/-3.1 versus 43.0+/-4.1%; P<0.05). This delayed protection was abrogated by prior inhibition of either PKC with chelerythrine chloride (5 mg/kg) or of TKs with lavendustin A (1.3 mg/kg), suggesting that both PKC and TK are crucial for the development of delayed preconditioning after A(1) receptor activation in the rabbit. Myocardial tissue extracts obtained 24 hours after CCPA treatment were analyzed for p38 MAPK catalytic activity using an in vitro kinase assay. This showed an almost 7-fold increase in p38 MAPK activity in myocardial samples pretreated with CCPA compared with control hearts. Two-dimensional gel electrophoresis revealed an increase in the phosphorylated isoforms of Hsp27 in hearts pretreated with CCPA compared with control hearts. Prior inhibition of either PKC or TK prevented the CCPA-induced increase in p38 MAPK activity and phosphorylation of Hsp27. This study identifies new components of the signaling mechanism of A(1)R-induced delayed preconditioning. Our results suggest an important role for both PKC and TK as mediators of late preconditioning against infarction after A(1)R activation and, although correlative, point to the p38 MAPK/Hsp27 pathway as a potential distal effector of this protection.
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PMID:Adenosine A(1) receptor induced delayed preconditioning in rabbits: induction of p38 mitogen-activated protein kinase activation and Hsp27 phosphorylation via a tyrosine kinase- and protein kinase C-dependent mechanism. 1080 61

Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue necrosis induced by a subsequent prolonged ischemia. It is hoped that elucidation of the mechanism for preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals. The combined effect of the release of these substances on G proteins and the cell's phospholipases induces the translocation and activation of the epsilon isozyme of protein kinase C. Protein kinase C appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that this cascade contains at least one tyrosine kinase and ultimately leads to the activation of p38 mitogen-activated protein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-activated protein kinase-activated protein kinase 2. Mitogen-activated protein kinase-activated protein kinase 2 phosphorylates HSP27, a 27-kDa heat shock protein that controls actin filament polymerization, and, therefore, affects the integrity of the cytoskeleton. Finally, mitochondrial adenosine 5'-triphosphate-sensitive K+ channels open, and the latter may be the final mediator of protection for ischemic preconditioning. The protective pathway has many built-in redundancies, perhaps creating a safety factor. These redundancies may also explain some of the species-related differences seen in ischemic preconditioning in which one redundant pathway may predominate over another.
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PMID:Ischemic preconditioning: from adenosine receptor to KATP channel. 1084 85

When the heart is subjected to a transient nonlethal period of ischemia, it quickly adapts itself to become resistant to infarction from a subsequent ischemic insult. This adaptation is called preconditioning. This cardioprotection has been shown to be mediated by stimulation of receptors linked to protein kinase C (PKC) (adenosine, bradykinin, opioids, etc.), and these receptors protect by activating PKC. PKC appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in the preconditioned heart. Recent studies imply that p38 mitogen-activated protein kinase carries the signal from PKC to the mitochondrial K(ATP) channels, causing them to open and thus protect the heart. The cardioprotection of preconditioning occurs in all species tested to date, and possibly also humans. It is expected that as the mechanism of preconditioning is more thoroughly understood, pharmacological preconditioning will become practical for clinical use.
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PMID:Ischemic preconditioning: from basic mechanisms to clinical applications. 1088 11

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