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)

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to coronary, carotid, or peripheral arteries promotes excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently, inadequate therapeutic approaches to stroke and coronary artery disease (CAD) are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions among platelets and other blood cells. This led to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by different cell types that could not individually synthesize the metabolite(s). Endothelium controls platelet reactivity via at least three biochemical systems: autacoids leading to production of prostacyclin and nitric oxide (NO) and endothelial ecto-adenosine phosphatase (ADPase)/CD39/nucleoside triphosphate diphosphohydrolase (NTPDase-1). The autacoids are fluid phase reactants, not produced by tissues in the basal state, but are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, they exert fleeting actions in the immediate milieu and are rapidly inactivated. CD39 is an integral component of the endothelial cell (EC) surface and is substrate activated. It maintains vascular fluidity in the complete absence of prostacyclin and NO, indicating that the latter are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient and local action and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in animal models. It metabolically neutralizes a prothrombotic releasate via deletion of ADP-the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced adenosine triphosphate (ATP)- and ischemia-induced norepinephrine release in the heart. This action can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in cd39 null mice. Thus, CD39 represents the next generation of cardioprotective and cerebroprotective molecules. This article focuses on our interpretations of recent data and their implications for therapeutics.
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PMID:Role of CD39 (NTPDase-1) in thromboregulation, cerebroprotection, and cardioprotection. 1585 26

Gap junctions are a unique type of intercellular junction that mediate the direct exchange of small molecules between neighboring cells and play critical roles in the normal function of numerous organs. Mutations in the connexin proteins that make up gap junctions have been implicated in numerous human skin and neurosensory disorders. The ability of gap junctions to transmit molecules between cells is regulated by intracellular pH, the phosphorylation state of connexin, and the interaction of connexin with other cellular proteins. This Perspective focuses on the novel and complex events initiated by intracellular acidification resulting from tissue ischemia or hypoxia that lead to the interruption of intercellular communication between astrocytes. These events include alterations in connexin43 (Cx43) phosphorylation, disruption of beta-actin binding to Cx43, and the induced interaction of Cx43 with the c-Src tyrosine kinase, extracellular signal-regulated kinase 1 and 2, and mitogen-activated protein kinase phosphatase 1.
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PMID:c-Src: bridging the gap between phosphorylation- and acidification-induced gap junction channel closure. 1599 70

Brief, nonlethal episodes of ischemia in the mammalian heart provide cardioprotection against the detrimental effects of a longer duration ischemia. The manifestation of this preconditioning (PC) phenomenon is initiated by the enhanced phosphorylation state of signal transduction proteins. We reported previously that PC is decreased in the aged rat myocardium. Although the mechanism responsible for this loss is not understood, a reduction in the phosphorylation of critical proteins associated with PC may be postulated. Experiments were conducted to investigate whether PC in the aged heart can be restored with the inhibition of endogenous protein phosphatases thereby enhancing phosphorylation of signaling proteins. Levels of phosphatase activities were also assessed with adult heart aging. Hearts from young adult (3-4 mo.) and aged (21-22 mo.) Fischer-344 rats were perfused in the presence or absence of okadaic acid (OKA; 0.1 microM). Aged adult hearts were either not preconditioned or were preconditioned with two PC cycles (5 min ischemia/5 min reperfusion). Myocardial cellular death that developed with a subsequent ischemia was determined with triphenyltetrazolium. With PC, 55% of the aged heart after ischemia was no longer viable. OKA administered before or after ischemia reduced this ischemia-induced cellular death by 29%. Without PC, OKA reduced viability 18% only when present before and after the ischemic episode. OKA in the ischemic young heart during reperfusion reduced the loss of viability 31%. The Protein Phosphatase 2A (PP2A) activity was found to be up to 82% greater in ventricular myocardium of aged rats. In conclusion, aging-induced changes in protein dephosphorylation may be one mechanism reducing the manifestation of preconditioning in the aged heart.
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PMID:Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. 1609 93

The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20microM) and ARA (20microM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia.
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PMID:Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. 1621 66

Ischemic preconditioning (IPC), a brief period of ischemia and reperfusion (I/R), generates profound but transient protection against a subsequent prolonged ischemic episode. The serine-threonine kinase Akt has been shown to mediate IPC, and Akt activation is negatively regulated by the phosphatase PTEN, but whether PTEN activity is modulated by IPC has not been investigated. When isolated, perfused rat hearts were subjected to an IPC stimulus consisting of 15-minute ischemia and 30-minute reperfusion (I-15/R-30), PTEN protein levels and activity were decreased, and levels of phospho-AKT were increased, relative to nonischemic hearts. Hearts subjected to IPC demonstrated improved recovery of cardiac function when subsequently subjected to I-30/R-45 as compared with hearts subjected to I-30/R-45 without prior IPC. When hearts were subjected to I-15 followed by R-30, R-60, or R-120, PTEN reaccumulated gradually and its activity was restored. Phospho-Akt levels at R-120 were decreased and these hearts were no longer protected against injury when subjected to I-30/R-45. Wortmannin administration during reperfusion blocked Akt activation and PTEN reaccumulation. In ischemic hearts, PTEN was rapidly degraded. Pretreatment with proteasome inhibitor MG132 blocked ischemia-induced degradation of PTEN and blocked IPC. Reperfusion following I-15 induced oxidation of the remaining PTEN, leading to Akt activation. Perfusion of H2(O2) was sufficient to induce Akt activation. Thus, loss of PTEN activity leads to induction of IPC and feedback mechanisms designed to ensure that Akt activation is transient are responsible for decay of IPC.
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PMID:PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. 1691 96

The wood frog, Rana sylvatica, survives weeks of whole body freezing during winter hibernation, expressing numerous metabolic adaptations that deal not only with freezing but with its consequences including organ ischemia and cellular dehydration. The present study analyzes the 20s multicatalytic proteinase (MCP) complex from skeletal muscle to determine how protein degradation is managed in the ischemic frozen state. MCP was partially purified and assayed fluorometrically using three AMC-labeled substrates to compare multiple states: control (5 degrees C acclimated), 24 h frozen at -2.5 degrees C, 4 or 8 h thawed at 5 degrees C, 8 h anoxia, and 40% dehydration. MCP from frozen frogs showed significantly different K(m) and V(max) values compared with controls; e.g., K(m) Z-LLE-AMC increased by 45% during freezing and 52% under anoxia whereas V(max) decreased by 40%. After thawing, K(m) was restored and V(max) rose by 2.2-fold. Incubations promoting protein kinase or phosphatase action on MCP showed that phosphatase treatment strongly increased V(max) implicating reversible phosphorylation in MCP regulation during freeze-thaw. Western blotting showed a 36% decrease in MCP protein in muscle from frozen frogs. The 20s MCP preferentially degrades oxidatively-damaged proteins and evidence of impaired function during freezing came from a 1.4-fold increase in protein carbonyl content in muscle and liver during freezing. Ubiquitin and ubiquitin conjugate levels were unchanged in muscle but changed markedly in liver during freeze-thaw.
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PMID:Vertebrate freezing survival: Regulation of the multicatalytic proteinase complex and controls on protein degradation. 1644 58

Cells have the capability of defending themselves from various stressors by activating a genetic program with the production of substances known as heat shock proteins (Hsps) and their regulatory partners, the heat shock transcription factors. Hsps play a major role in systemic hypertension, coronary artery disease, carotid atherosclerosis, myocardial infarction and myocardial ischemia. In this review we discuss the interaction between Hsp70 and CaN which was carried out in our laboratory. We demonstrated that the cardiac Hsp70 stimulated a 2-fold increase in calcineurin (CaN) activity. In addition, the pull-down assay revealed that Hsp70 directly interacts with CaN. Furthermore, expressed cardiac specific Hsp70 was phosphorylated in vitro by cAMP-dependent protein kinase. The phosphorylated Hsp70 was unable to activate the phosphatase activity of CaN. For the first time we demonstrated that Hsp70 is phosphorylated by cAMP-dependent protein kinase and provides an on/off switch for the regulation of CaN signaling by Hsp70. This will lead to therapeutic benefit in human diseases such as atherosclerosis, cardiomyopathy, congestive heart failure, and ischemia.
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PMID:Interaction between heat shock protein 70 kDa and calcineurin in cardiovascular systems (Review). 1646 87

The aim of this study was to assess the influence of ischemic preconditioning (IPC) on parenchymal liver blood flow during the early phase of reperfusion after 60 minutes of ischemia, additionally modified by adding N-nitro-L-arginine methyl ester (L-NAME). Our research involved 4 groups of rats (10 animals in each group), which underwent liver ischemia and 24 hours of reperfusion. Group I, ischemia/reperfusion (IR) was performed; group II, IPC, 10 minutes of ischemia and 10 minutes of reperfusion, and IR after that; group III, L-NAME (10 mg/kg intravenous [iv]), 10 minutes before IR; and group IV, L-NAME before IPC + IR. Activity of APAT, ALAT, GGTP, and FA was marked in serum in 90 minutes and 24 hours of reperfusion. In the liver biopsies at 24 hours of reperfusion, we analyzed reaction on adenosine-3-phosphatase stimulated by Mg++ and performed histological examination. The parenchymal perfusion was measured using a laser-doppler blood flowmeter (model PeriFlux System5000, Perimed Inc., United Kingdom). IPC during reperfusion led to minor injuries of the organ, with statistically significant normalization of enzymes compared with group 1, and a better reaction to the adenosine-3-phosphatase IPC produced faster and full return of perfusion to the 68.3 value at 24 hours (59.1 in the 60 minutes). In groups III and IV at 60 minutes, the perfusion was not statistically different from that in group 1. IPC causes full and faster blood return in the early phase of reperfusion and minor injury of liver parenchyma and liver sinus. The protective effect observed, especially in the first 60 minutes of reperfusion, was limited by L-NAME and was influenced by the action of nitric oxide.
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PMID:Influence of ischemic preconditioning and nitric oxide on microcirculation and the degree of rat liver injury in the model of ischemia and reperfusion. 1650 1

The sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) is under the control of an SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a, whereas phosphorylation of PLN at either the Ser16 site by PKA or the Thr17 site by CaMKII reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca2+ uptake by the SR. This leads to an increase in the velocity of relaxation, SR Ca2+ load and myocardial contractility. In the intact heart, beta-adrenoceptor stimulation results in phosphorylation of PLN at both Ser16 and Thr17 residues. Phosphorylation of the Thr17 residue requires both stimulation of the CaMKII signaling pathways and inhibition of PP1, the major phosphatase that dephosphorylates PLN. These two prerequisites appear to be fulfilled by beta-adrenoceptor stimulation, which as a result of PKA activation, triggers the activation of CaMKII by increasing intracellular Ca2+, and inhibits PP1. Several pathological situations such as ischemia-reperfusion injury or hypercapnic acidosis provide the required conditions for the phosphorylation of the Thr17 residue of PLN, independently of the increase in PKA activity, i.e., increased intracellular Ca2+ and acidosis-induced phosphatase inhibition. Our results indicated that PLN was phosphorylated at Thr17 at the onset of reflow and immediately after hypercapnia was established, and that this phosphorylation contributes to the mechanical recovery after both the ischemic and acidic insults. Studies on transgenic mice with Thr17 mutated to Ala (PLN-T17A) are consistent with these results. Thus, phosphorylation of the Thr17 residue of PLN probably participates in a protective mechanism that favors Ca2+ handling and limits intracellular Ca2+ overload in pathological situations.
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PMID:The importance of the Thr17 residue of phospholamban as a phosphorylation site under physiological and pathological conditions. 1664 92

Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.
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PMID:NMDA receptors and the differential ischemic vulnerability of hippocampal neurons. 1681 62


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