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 activities of Ca2+/calmodulin (CaM)-dependent, Ca2+/phospholipid-dependent, and cyclic AMP-dependent protein kinases (CaM-KII, PKC, and PKA, respectively) were determined in rat brains after global ischemia. Both CaM-KII and PKC activities were significantly depressed in both hippocampal and cerebral cortical regions of ischemic animals, whereas no change was detected in PKA activity. The loss of CaM-KII activity was more dramatic and more sustained than the loss of PKC activity and correlated with the duration of ischemia. These decreases in enzyme activity were found in both supernatant and pellet fractions from crude homogenates. When the supernatant and pellet were analyzed for the amount of CaM-KII 50-kDa protein, a significant decrease was detected in supernatant fractions that paralleled a gain in the amount of CaM-KII in the pellet. Thus, the loss of CaM-KII activity in the supernatant can be explained by translocation of the enzyme to the pellet. Whether inactivation of CaM-KII occurs during or after the enzyme translocates from the supernatant to the pellet is unknown. Our results indicate that loss in CaM-KII activity parallels neuronal damage associated with ischemia; down-regulation of CaM-KII activity coincided with translocation of the enzyme to the particulate fraction, and it is proposed that this may be, in fact, a mechanism for controlling excessive CaM-KII phosphorylation.
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PMID:Ischemia-induced translocation of Ca2+/calmodulin-dependent protein kinase II: potential role in neuronal damage. 131 52

Many investigations have shown that calcium and adenosine triphosphate are crucial to central nervous system functions. It is probable that alterations of these substances during central nervous system ischemia are involved in the processes that cause irreversible neural damage. Calcium regulates several protein kinases that are responsible for phosphorylation of proteins vital for many central nervous system functions. Using a rabbit spinal cord ischemia model, we found protein kinase C and calcium/calmodulin-dependent kinase were severely affected during the first hour of ischemia. Protein kinase A was not significantly affected. The time course of lost protein kinase C enzyme activity closely corresponded to irreversible loss of neurologic function, and there is evidence that protein kinase C inhibitor activity is generated. Also, drugs that inhibit protein kinase C increased neurologic damage when administered during the early phases of ischemia. These results suggest that protein phosphorylation, particularly by protein kinase C, is critical to maintenance of neurologic function.
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PMID:Protein phosphorylation during ischemia. 223 67

The protein serine/threonine kinases which are highly expressed in the central nervous system (CNS) are severely affected by brain ischemia. Irrespective of substantial differences among the particular members of this group of kinases, their responses to ischemic stress show a lot of similarities. Initially they are switched on by facilitated interaction with their specific activators/second messengers like cyclic AMP, 1,2-sn-diacylglicerol and particularly Ca2+, then they are translocated to highly specific regions of plasma membranes. After phosphorylation of target proteins, the kinases are deactivated by means of different routes. Activity of PKA is regulated by its direct access to cAMP. In the case of CaMKII, it is probably achieved by its extensive, inhibitory autophosphorylations, while PKC seems to be proteolytically degraded. These biphasic changes in serine/threonine kinases activity may play a critical role in the evolution of postischemic brain injury and provide a mechanism for a variety of short- and long-term signalling events.
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PMID:Protein serine/threonine kinases (PKA, PKC and CaMKII) involved in ischemic brain pathology. 876 9

We tested the hypothesis that altered phosphorylation of myofibrillar proteins is involved in post-ischemic myocardial stunning. Myofibrillar proteins were isolated from Langendorff perfused control rabbit hearts, hearts submitted to 15 min normothermic ischemia and hearts submitted to 15 min ischemia followed by 10 min of reperfusion (stunned hearts). The in vivo level of phosphorylation of specific contractile proteins by protein kinases A and C was indirectly detected by the amount of 32P incorporated in vitro in the presence of these protein kinases and saturating concentration of [gamma-32P]-ATP (back-phosphorylation method). In control experiments the back-phosphorylation technique was able to detect PKA- or PKC-induced protein phosphorylation in hearts treated with isoproterenol and phorbol ester, respectively. In stunned hearts, contractile function was significantly suppressed compared to the period before ischemia. We found no difference in myofibrillar protein profile (on densitometry of the Coomassie-stained gels after SDS-PAGE) and in PKA mediated 32P incorporation when comparing control, ischemic and stunned myocardium. Three different PKCs were used for phosphorylation: commercial purified rat brain PKC, partially purified rat brain PKC or rabbit partially purified cardiac PKC. Cardiac PKC mainly phosphorylated troponin I, whereas brain PKC phosphorylated both troponin T and troponin I. No significant difference in 32P incorporation mediated by either brain or cardiac PKC was found between control, ischemic and ischemic/reperfused myofibrils. These data indicate that myocardial stunning does not cause changes in PKC- or PKA-mediated Pi incorporation into myofibrillar proteins detectable by the back-phosphorylation method.
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PMID:Phosphorylation by protein kinases A and C of myofibrillar proteins in rabbit stunned and non-stunned myocardium. 944 26

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to beta-adrenergic stimulation was significantly decreased both in P and NP hearts.
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PMID:Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a beta-adrenergic challenge. 1457 98

Regulation of the Na/K ATPase by protein kinases is model-specific. We have observed a profound activation of the sarcolemmal Na/K ATPase during cardiac ischemia, which is masked by an inhibitor of the enzyme in the cytosol. The aim of these studies was to characterize the pathways involved in this activation in the Langendorff-perfused rat heart. Na/K ATPase activity was determined by measuring ouabain-sensitive phosphate generation by cardiac homogenates at 37 degrees C. In isolated sarcolemma, ischemia (30 min) caused a substantial activation of the Na/K ATPase compared with aerobic controls, which was abolished by perfusing the heart with staurosporine or H89. However, the alpha1 subunit of the Na/K ATPase was not phosphorylated during ischemia. The sarcolemmal protein phospholemman (PLM) was found associated with the Na/K ATPase alpha1 and beta1 but not alpha2 subunits, and PLM increased its association with the catalytic subunit of PKA following ischemia. In vitro 14-3-3 binding assays indicated that PLM was phosphorylated following ischemia. These results indicate that the ischemia-induced activation of the Na/K ATPase is indirect, through phosphorylation of PLM, which is an integral part of the Na/K ATPase enzyme complex in the heart. The role of PLM is analogous to phospholamban in regulating the sarcoplasmic reticulum calcium ATPase.
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PMID:Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K-ATPase. 1459 63

Recent evidence suggests that impaired insulin/insulin-like growth factor I (IGF-I) input may be associated to neurodegeneration. Several major neurodegenerative diseases involve excitotoxic cell injury whereby excess glutamate signaling leads to neuronal death. Recently it was shown that glutamate inactivates Akt, a serine-kinase crucially involved in the prosurvival actions of IGF-I. We now report that excitotoxic doses of glutamate antagonize Akt activation by IGF-I and inhibit the neuroprotective effects of this growth factor on cultured neurons. Glutamate induces loss of sensitivity to IGF-I by phosphorylating the IGF-I receptor docking protein insulin-receptor-substrate (IRS)-1 in Ser(307) through a pathway involving activation of PKA and PKC in a hierarchical fashion. Administration of Ro320432, a selective PKC inhibitor, abrogates the inhibitory effects of glutamate on IGF-I-induced Akt activation in vitro and in vivo and is sufficient to block the neurotoxic action of glutamate on cultured neurons. Notably, administration of Ro320432 after ischemic insult, a major form of excitotoxic injury in vivo, results in a marked decrease ( approximately 50%) in infarct size. Therefore, uncoupling of IGF-I signaling by glutamate may constitute an additional route contributing to excitotoxic neuronal injury. Further work should determine the potential use of PKC inhibitors as a novel therapeutic strategy in ischemia and other excitotoxic insults.
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PMID:Glutamate excitotoxicity attenuates insulin-like growth factor-I prosurvival signaling. 1469 66

Protection against ischemia by ischemic preconditioning (IP) is seen in many tissues and organs. However, the preconditioning ischemia must precede lethal ischemia for this effect to occur, and the creation of ischemia to treat heart disease does not seem to be a realistic strategy. Accordingly, the underlying mechanisms that confer cardioprotection should be identified. Early studies revealed that IP causes two windows of cardioprotection, and subsequent efforts to detect cardioprotective factors have identified various triggers, mediators, and potent effectors of IP, such as endogenous receptor agonists (adenosine, catecholamines, bradykinin, and opioids), intracellular messengers [protein kinase C (PKC), p38MAPK, PI-3K, and PKA], ion channels such as KATP channels, enzymes including heat shock proteins (HSPs), superoxide dismutase (SOD), and 5'-nucleotidase, and other factors [nitric oxide (NO), growth factors, free radicals, and products of the arachidonic acid cascade]. Some of these factors are involved in several different pathways and may have multiple roles in IP-induced cardioprotection. Recently, however, certain problems have arisen such as controversies related to increasing knowledge and the relative lack of clinical studies in contrast to the intensive performance of basic studies. To overcome these problems, the latest studies have followed three major trends: (1) investigation of mechanisms to explain the current controversies, (2) detection of other unknown potent mechanisms, and (3) promotion of clinical trials based on the evidence from experimental studies in larger animals. Here, we summarize recent investigations on IP, emphasizing on the controversial issues and emerging factors, and discuss current research on the prevention or treatment of ischemic heart disease including some relevant clinical studies.
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PMID:Ischemic preconditioning: emerging evidence, controversy, and translational trials. 1545 94

Pituitary adenylate cyclase activating polypeptide (PACAP) exerts neuroprotective effects in various in vitro and in vivo models of cerebral pathologies. It has been shown that PACAP protects neurons in rat models of both global and focal ischemia. In the present study, we investigated factors that may play a role in the neuroprotective effects of PACAP. PACAP strongly reduced the anisomycin-induced apoptosis of PC12 cells, which was abolished in a PKA-deficient PC12 cell line (A126). This effect was also observed in vivo, in permanent occlusion of the middle cerebral artery, where the number of TUNEL-positive neurons was significantly reduced in the ischemic core of PACAP-treated animals. Our results show that PACAP has a minor antioxidant effect in a non-cellular in vitro system, and has considerable antioxidant effects in an in vitro red blood cell filtration model. PACAP had no effect on platelet aggregation induced by collagen, ADP or epinephrine. Our results demonstrate that the effects of PACAP on delayed neuronal death may play a significant role in the reduction of the infarct size in vivo, but the antioxidant effect could only be observed at concentrations higher than that used in the model of focal ischemia.
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PMID:Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals. 1551 93

Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that when phosphorylated at Ser16 by PKA and/or at Thr17 by CaMKII increases the affinity of the SR Ca2+ pump for Ca2+. PLB is therefore, a critical regulator of SR function, myocardial relaxation and myocardial contractility. The present study was undertaken to examine the status of PLB phosphorylation after ischemia and reperfusion and to provide evidence about the possible role of the phosphorylation of Thr17 PLB residue on the recovery of contractility and relaxation after a period of ischemia. Experiments were performed in Langendorff perfused hearts from Wistar rats. Hearts were submitted to a protocol of global normothermic ischemia and reperfusion. The results showed that (1) the phosphorylation of Ser16 and Thr17 residues of PLB increased at the end of the ischemia and the onset of reperfusion, respectively. The increase in Thr17 phosphorylation was associated with a recovery of relaxation to preischemic values. This recovery occurred in spite of the fact that contractility was depressed. (2) The reperfusion-induced increase in Thr17 phosphorylation was dependent on Ca2+ entry to the cardiac cell. This Ca2+ influx would mainly occur by the coupled activation of the Na+ / H+ exchanger and the Na+ / Ca2+ exchanger working in the reverse mode, since phosphorylation of Thr17 was decreased by inhibition of these exchangers and not affected by blockade of the L-type Ca2+ channels. (3) Specific inhibition of CaMKII by KN93 significantly decreased Thr17 phosphorylation. This decrease was associated with an impairment of myocardial relaxation. The present study suggests that the phosphorylation of Thr17 of PLB upon reflow, may favor the full recovery of relaxation after ischemia.
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PMID:Phosphorylation of phospholamban in ischemia-reperfusion injury: functional role of Thr17 residue. 1552 73


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