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)

Transient global ischemia caused by 5 min of cardiac arrest induced delayed neuronal cell death (apoptosis) in the CA1 region of the rat hippocampus. To characterize the molecular mechanisms that regulate apoptosis in vivo, the contributions to cell death of mitogen-activated protein kinase family members were examined in the hippocampal region after brain ischemia-reperfusion. Ischemia-reperfusion led to a strong activation of the JNK/SAPK (c-Jun NH2-terminal protein kinase/stress activated protein kinase), ERK (extracellular signal-regulated kinase), and p38 enzymes. These results with other previous studies suggest that the activation of JNK/SAPK in accordance with p38 contributes to the induction of apoptosis in CA1 neurons.
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PMID:Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. 1007 72

The AMP-activated protein kinase (AMPK) is a member of a metabolite-sensing protein kinase family that is found in all eukaryotes. AMPK activity is regulated by vigorous exercise, nutrient starvation and ischemia/hypoxia, and modulates many aspects of mammalian cell metabolism. The AMPK yeast homolog, Snf1p, plays a major role in adaption to glucose deprivation. In mammals, AMPK also has diverse roles that extend from energy metabolism through to transcriptional control.
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PMID:Dealing with energy demand: the AMP-activated protein kinase. 1008 18

Tonometric measurements of colonic and gastric mucosa pH are used as indirect determinants of splanchnic perfusion in shocked patients or those undergoing aortic cross-clamp. Mucosal acidification in response to splanchnic vasodilators such as dopamine has been assumed to signify ischemia. However, cellular acidification may occur independent of oxygenation and the direct effects of dopamine on mucosal acid-base are unknown. We examined the effects of dopamine on cellular pH (independent of oxygenation) of intestinal mucosa in vitro. Crypts isolated from the distal colon of Sprague-Dawley rats were loaded with a pH-sensitive fluorescent probe, perfused with a Hepes-buffered Ringers solution, and imaged with confocal laser scanning microscopy. In separate experiments, crypts were loaded with a calcium-sensitive probe (Fura-2) and concentrations of free cytosolic calcium were measured with fluorescence imaging. Dopamine perfusion produced a reversible cytosolic acidification of crypts which was not significantly affected by (i) the nominal absence of bicarbonate, (ii) alpha- and beta-adrenergic receptor blockade, or (iii) protein kinase C inhibition. Dopamine did not significantly affect intracellular calcium concentrations. However, dopamine-induced acidification was inhibited by (a) blocking sodium-hydrogen exchange with amiloride, (b) prior exposure to adenosine 3', 5'-cyclic monophosphate (cAMP), or (c) protein kinase A blockade (all P < 0.01). Dopamine directly acidifies mucosal crypt cells in a mechanism that involves a cAMP-mediated inhibition of sodium-hydrogen exchange. This finding accounts for the acidification of intestinal mucosa during low-dose dopamine infusion despite a demonstrable improvement in splanchnic perfusion. Direct mucosal effects of pharmacological agents must be considered in the evaluation of perfusion parameters based on tonometric data.
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PMID:Direct effects of dopamine on colonic mucosal pH: implications for tonometry. 1021 Jun 44

Neurons can be preconditioned against ischemic damage by a brief sublethal period of ischemia, applied several days before the second insult. Here we report on changes in the distribution and the levels of protein kinase Cgamma (PKCgamma) in nonconditioned and preconditioned rat hippocampal CA1 and neocortex regions after a 9 min ischemic episode induced by two-vessel occlusion ischemia. At the end of the second ischemia we found significantly lower levels of PKCgamma in the CA1 region but not neocortex of preconditioned brains than in non-conditioned brains. Protein kinase Cgamma levels in both CA1 and neocortex decrease simultaneously in the cytosolic fractions. We conclude that PKCgamma is translocated to cell membranes during ischemia and is rapidly removed or degraded during the second otherwise lethal ischemic insult in preconditioned brains. The data suggest that ischemic preconditioning enhances downregulation of cell signaling mediated by PKCgamma and may thereby provide neuroprotection.
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PMID:Rapid decline in protein kinase Cgamma levels in the synaptosomal fraction of rat hippocampus after ischemic preconditioning. 1032 62

Cyclin-dependent kinase 5 (cdk5) is a homologue of cell division cycle 2 (cdc2)-like protein kinase. It is mainly expressed in neurons, and supposed to be involved in the dynamic change of neurocytoskeleton structure seen in the brain after ischemia. In the present study, we investigated immunoreactivity for cdk5 and its critical regulatory subunit p35 in rat brain after 90 min of middle cerebral artery (MCA) occlusion. In the control brain, immunoreactive cdk5 was present in some neurons, while p35 was evident in almost all neurons. At 1 h after blood flow restoration, both of them were remarkably increased in the MCA territory. At 3 h, both immunoreactivities were decreased in the ischemic core region, while they became stronger in neurons at the boundary zone of the MCA territory, which decreased thereafter. These results might suggest that increased cdk5 activity in the brain after ischemia caused depolymerization of neurocytoskeletons, which resulted in neuronal cell death.
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PMID:Expression of cyclin-dependent kinase 5 and its activator p35 in rat brain after middle cerebral artery occlusion. 1032

A short period of sublethal preconditioning ischemia (3 min) followed by two days of reperfusion provides almost complete protection against ischemic cell death induced by a second (9 min) lethal ischemic episode. Here, we have investigated the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase, two kinases known to activate gene transcription and to be of importance for cell survival, after sublethal preconditioning ischemia in the rat hippocampal CA1 region. The activation levels of these two kinases were also studied after a second ischemic episode both in preconditioned and nonconditioned brains. An increased phosphorylation of the extracellular signal-regulated protein kinase kinase was found in neuronal cell bodies, particularly in the nucleus, 30 min, 4 h and two days of reperfusion after preconditioning ischemia. Two days after preconditioning ischemia both extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase were markedly phosphorylated. During the early reperfusion period (30 min) after the second ischemic insult the phosphorylation levels of these two kinases were increased in both nonconditioned and preconditioned brains. In the late reperfusion time (one day), the phosphorylation levels of the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase were decreased in preconditioned brains, but remained elevated in nonconditioned brains. We conclude that phosphorylation of the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase after sublethal ischemia correlates with the neuroprotection induced by preconditioning, possibly by transcriptional activation of neuroprotective genes. Also, preconditioning enhances normalization of the disturbed cell signaling through the extracellular signal-regulated protein kinase cascade induced by lethal ischemia.
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PMID:Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning. 1043 Apr 72

Although the sarcoplasmic reticulum (SR) is known to regulate the intracellular concentration of Ca2+ and the SR function has been shown to become abnormal during ischemia-reperfusion in the heart, the mechanisms for this defect are not fully understood. Because phosphorylation of SR proteins plays a crucial role in the regulation of SR function, we investigated the status of endogenous Ca2+/calmodulin-dependent protein kinase (CaMK) and exogenous cAMP-dependent protein kinase (PKA) phosphorylation of the SR proteins in control, ischemic (I), and ischemia-reperfused (I/R) hearts treated or not treated with superoxide dismutase (SOD) plus catalase (CAT). SR and cytosolic fractions were isolated from control, I, and I/R hearts treated or not treated with SOD plus CAT, and the SR protein phosphorylation by CaMK and PKA, the CaMK- and PKA-stimulated Ca2+ uptake, and the CaMK, PKA, and phosphatase activities were studied. The SR CaMK and CaMK-stimulated Ca2+ uptake activities, as well as CaMK phosphorylation of Ca2+ pump ATPase (SERCA2a) and phospholamban (PLB), were significantly decreased in both I and I/R hearts. The PKA phosphorylation of PLB and PKA-stimulated Ca2+ uptake were reduced significantly in the I/R hearts only. Cytosolic CaMK and PKA activities were unaltered, whereas SR phosphatase activity in the I and I/R hearts was depressed. SOD plus CAT treatment prevented the observed alterations in SR CaMK and phosphatase activities, CaMK and PKA phosphorylations, and CaMK- and PKA-stimulated Ca2+ uptake. These results indicate that depressed CaMK phosphorylation and CaMK-stimulated Ca2+ uptake in I/R hearts may be due to a depression in the SR CaMK activity. Furthermore, prevention of the I/R-induced alterations in SR protein phosphorylation by SOD plus CAT treatment is consistent with the role of oxidative stress during ischemia-reperfusion injury in the heart.
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PMID:Status of Ca2+/calmodulin protein kinase phosphorylation of cardiac SR proteins in ischemia-reperfusion. 1048 25

O(2) deprivation induces membrane depolarization in mammalian central neurons. It is possible that this anoxia-induced depolarization is partly mediated by an inhibition of K(+) channels. We therefore performed experiments using patch-clamp techniques and dissociated neurons from mice neocortex. Three types of K(+) channels were observed in both cell-attached and inside-out configurations, but only one of them was sensitive to lack of O(2). This O(2)-sensitive K(+) channel was identified as a large-conductance Ca(2+)-activated K(+) channel (BK(Ca)), as it exhibited a large conductance of 210 pS under symmetrical K(+) (140 mM) conditions, a strong voltage-dependence of activation, and a marked sensitivity to Ca(2+). A low-O(2) medium (PO(2) = 10-20 mmHg) markedly inhibited this BK(Ca) channel open probability in a voltage-dependent manner in cell-attached patches, but not in inside-out patches, indicating that the effect of O(2) deprivation on BK(Ca) channels of mice neocortical neurons was mediated via cytosol-dependent processes. Lowering intracellular pH (pH(i)), or cytosolic addition of the catalytic subunit of a cAMP-dependent protein kinase A in the presence of Mg-ATP, caused a decrease in BK(Ca) channel activity by reducing the sensitivity of this channel to Ca(2+). In contrast, the reducing agents glutathione and DTT increased single BK(Ca) channel open probability without affecting unitary conductance. We suggest that in neocortical neurons, (a) BK(Ca) is modulated by O(2) deprivation via cytosolic factors and cytosol-dependent processes, and (b) the reduction in channel activity during hypoxia is likely due to reduced Ca(2+) sensitivity resulting from cytosolic alternations such as in pH(i) and phosphorylation. Because of their large conductance and prevalence in the neocortex, BK(Ca) channels may be considered as a target for pharmacological intervention in conditions of acute anoxia or ischemia.
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PMID:O(2) deprivation inhibits Ca(2+)-activated K(+) channels via cytosolic factors in mice neocortical neurons. 1048 72

Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
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PMID:EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits. 1051 71

Endothelial cell (EC) injury induced by reactive oxygen species (ROS) was investigated and effects of Ca(2+) channel blockers, agents which elevate intracellular cAMP levels ([cAMP](i)), and protein kinase inhibitors on H(2)O(2)-induced EC injury were analyzed using human umbilical vein EC cultures. Exposure to H(2)O(2) increased intracellular Ca(2+) levels and decreased [cAMP](i). Ca(2+) channel blockers, [cAMP](i)-elevating agents, and protein kinase inhibitors significantly inhibited H(2)O(2)-induced EC injury. Data suggest that H(2)O(2)-induced EC injury is mediated by extracellular Ca(2+) influx, intracellular cAMP efflux, and intracellular signaling, each of which is blocked by Ca(2+) channel blockers, [cAMP](i)-elevating agents, or protein kinase inhibitors. It is suggested that ischemia/reperfusion injury induced by ROS may be prevented by Ca(2+) channel blockers, [cAMP](i)-elevating agents, and protein kinase inhibitors.
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PMID:Prevention of reactive oxygen-induced endothelial cell injury by blocking its process. 1052 52


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