Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Ischemic preconditioning: from adenosine receptor to KATP channel. 1084 85

We have investigated whether translocation of constitutive low molecular weight stress proteins (alphaB-crystallin and HSP27) to the myofilament/cytoskeletal compartment occurs during ischemic preconditioning and assessed if this is causally associated with cardioprotection. Triton-insoluble preparations from fresh or aerobically perfused rat hearts (n=4/group) contained relatively little alphaB-crystallin (96 +/- 43 and 43 +/- 36 units respectively) or HSP27 (177 +/- 32 and 101 +/- 26 units respectively). Three preconditioning cycles of (5 min ischemia + 5 min reperfusion) increased the Triton-insoluble crystallin to 864 +/- 61 units (P<0.05) and HSP27 to 1353 +/- 53 units (P<0.05). Two hours of aerobic perfusion following the preconditioning protocol resulted the return of alphaB-crystallin and HSP27 to near control levels (189 +/- 14 units and 252 +/- 24 units, respectively). Stress protein translocation, comparable to that achieved by the IPC protocol was induced by aerobic perfusion with hypercarbic (pH 6.8) perfusion. Thus, three cycles of 5 min hypercarbia + 5 min normocarbia increased alphaB-crystallin to 628 +/- 30 units (P<0.05) and HSP27 to 1353 +/- 53 units. In parallel functional studies, the recovery of LVDP after 35 min ischemia and 60 min of reperfusion was 43 +/- 7% in the ischemic control group, 61 +/- 3% (P<0.05) in the preconditioned group and 42 +/- 6% in the hypercarbic group. Thus, translocation of alphaB-crystallin and/or is not of-itself sufficient to induce cardioprotection. Using a phospho-specific antibody, we have demonstrated that preconditioning not only translocates alphaB-crystallin but also increases its phosphorylation at Ser-59 by 9.7-fold compared to aerobic controls (1616 +/- 402 v 166 +/- 28 units respectively). In contrast, hypercarbia while eliciting a comparable translocation, failed to alter the phosphorylation state of alphaB-crystallin. Preconditioning-induced phosphorylation was significantly attenuated by 50 microM genistein (by 61%), 10 microM SB203580 (by 91%) and 10 microM bisindolylmaleimide (by 68%), but not by 10 microM PD98059 (by 4%). Our findings are consistent with the possibility that ischemic preconditioning may be mediated by phosphorylation and translocation of constitutive low molecular weight stress proteins, particularly alphaB-crystallin.
 ...
PMID:Ischemic preconditioning: a potential role for constitutive low molecular weight stress protein translocation and phosphorylation? 1088 50

Extracellular adenosine (Ado) accumulates during brain ischemia. To investigate the pathophysiological role of Ado on glial cells under ischemic conditions, we examined the effect of Ado on the survival of C6 glial cells exposed to chemical ischemia (CI). Treatment with Ado during exposure to CI showed a marked protective effect, that was mediated via intracellular transport and conversion of Ado to inosine (Ino). In contrast, Ado exacerbated CI-mediated cell death when it was added during the recovery time after exposure to CI. Ado cytotoxicity was largely mediated via intracellular transport, but conversion of Ado to Ino abolished its toxicity. Ado-induced cell death was characteristic of apoptosis, and Ado increased the expression of a pro-apoptotic product Bax but decreased that of an anti-apoptotic product Bcl-2. Ado also suppressed the induction of two stress proteins HSC70 and HSP27. Furthermore, Ado induced cytochrome c release and increased caspase-3-like activity. These results indicate the dual opposing effects of Ado on glial cell survival. Intracellular accumulation of Ado can be both cytoprotective and cytotoxic, depending on its metabolic pathway.
 ...
PMID:Opposing effects of adenosine on the survival of glial cells exposed to chemical ischemia. 1107 Apr 97

Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 micromol/L) only during IP blunted the infarct size limitation by IP (37.3+/-6.3% versus 7.4+/-2.1% in the IP group, P:<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3+/-9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.
 ...
PMID:Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart. 1115 69

Brain ischemia results in cellular degeneration and loss of function. Here we investigated the neuroprotective effect of lithium in an in vitro model of ischemia. Organotypic hippocampal slice cultures were exposed to oxygen and glucose deprivation. Cellular death was quantified by measuring uptake of propidium iodide (PI). Lithium chloride (0.2-1.2 mM) was added to the medium before, during and after lesion induction. A decrease in incorporation of PI was observed, indicating a neuroprotective effect in all doses tested. We also studied the effect of lithium on the phosphorylation of HSP27, a heat shock protein involved in cellular protection in its dephosphorylated state. In the lesioned hippocampus, 0.4 mM lithium chloride decreased the proportion of phosphorylated HSP27 to total HSP27. These results suggest that lithium may be useful in the treatment of brain ischemia.
 ...
PMID:An investigation of the neuroprotective effect of lithium in organotypic slice cultures of rat hippocampus exposed to oxygen and glucose deprivation. 1171 Dec 8

Pretreatment with phosphatase inhibitors did not affect the decrease in ATP content in endothelial cells, but inhibited HSP27 dephosphorylation and redistribution, damages to actin cytoskeleton, and morphological changes in cells. Our results suggest that inhibition of stress-induced HSP27 dephosphorylation protects cells from ischemia-induced damages.
 ...
PMID:Phosphatase inhibitors prevent HSP27 dephosphorylation, destruction of stress fibrils, and morphological changes in endothelial cells during ATP depletion. 1174 May 92

We have developed methods that allow detection, quantitation, purification, and identification of cardiac proteins S-thiolated during ischemia and reperfusion. Cysteine was biotinylated and loaded into isolated rat hearts. During oxidative stress, biotin-cysteine forms a disulfide bond with reactive protein cysteines, and these can be detected by probing Western blots with streptavidin-horseradish peroxidase. S-Thiolated proteins were purified using streptavidin-agarose. Thus, we demonstrated that reperfusion and diamide treatment increased S-thiolation of a number of cardiac proteins by 3- and 10-fold, respectively. Dithiothreitol treatment of homogenates fully abolished the signals detected. Fractionation studies indicated that the modified proteins are located within the cytosol, membrane, and myofilament/cytoskeletal compartments of the cardiac cells. This shows that biotin-cysteine gains rapid and efficient intracellular access and acts as a probe for reactive protein cysteines in all cellular locations. Using Western blotting of affinity-purified proteins we identified actin, glyceraldehyde-3-phosphate dehydrogenase, HSP27, protein-tyrosine phosphatase 1B, protein kinase Calpha, and the small G-protein ras as substrates for S-thiolation during reperfusion of the ischemic rat heart. MALDI-TOF mass fingerprint analysis of tryptic peptides independently confirmed actin and glyceraldehyde-3-phosphate dehydrogenase S-thiolation during reperfusion. This approach has also shown that triosephosphate isomerase, aconitate hydratase, M-protein, nucleoside diphosphate kinase B, and myoglobin are S-thiolated during post-ischemic reperfusion.
 ...
PMID:Detection, quantitation, purification, and identification of cardiac proteins S-thiolated during ischemia and reperfusion. 1177 20

Previous studies have shown that adult rat myocytes can be protected from simulated ischemia-reperfusion (I/R) injury by small heat shock proteins (sHSPs). However, to date the cardioprotective effect of sHSPs has not been confirmed in adult myocytes from a large animal species. Left ventricular myocytes from adult dogs were cultured and infected with a replication-deficient adenovirus designed to increase expression of the human form of HSP27. The response to simulated I/R injury was compared using morphologic criteria. Virus-infected myocytes expressed two- to threefold more HSP27 and sustained less injury in response to simulated I/R than control cells (P < 0.001; paired t-test). Canine myocytes can be isolated, cultured, and induced to increase the expression of a foreign protein without significant effects on differentiation and/or viability. Increased expression of HSP27 provides significant protection from simulated I/R injury in adult canine myocytes. Determining the mechanism by which sHSPs protect from lethal cell injury will provide important new insights into the mechanism of irreversible cell injury in adult myocardium.
 ...
PMID:Increased expression of HSP27 protects canine myocytes from simulated ischemia-reperfusion injury. 1183 89

Hypoxic preconditioning (HP) does not improve post-ischemic function in the hearts of aging rats secondary to failure of protein kinase C (PKC) activation, but the effect of heat shock (HS) or preconditioning has not been studied. We studied whether HS increases tolerance to ischemia and whether its combination with HP would restore the cardioprotective effect in aging rat hearts. HS was performed in 12- and 50-week-old rats. Hearts were isolated and subjected to HP by 10 min hypoxic perfusion before 25 min ischemia followed by 30 min reperfusion 48 h after HS. Both HP and HS improved recovery of left ventricular function with translocation of PKC-delta from the cytosol to the nuclear fraction and induction of heat shock proteins, HSP27, HSP70, and alphaB-crystallin. The combination of HS and HP enhanced the translocation of PKC-delta in young rats, resulting in further improvement in functional recovery. In older rats, HP translocated PKC-delta from the membrane to the cytosol fraction, but did not improve functional recovery, although the combination of HS with HP induced HS proteins and translocated PKC-delta from the cytosol to the nuclear fraction. HS provided cardioprotection and had additive effects to HP with additional PKC-delta activation in young rats. However, in hearts from aging rats, HS alone was not cardioprotective, nor was its combination with HP, despite the induction of HS proteins and the activation of PKC-delta, resulting in its translocation to the nuclear fraction.
 ...
PMID:Aging abolishes the cardioprotective effect of combination heat shock and hypoxic preconditioning in reperfused rat hearts. 1239 11

Diverse physiological stresses (e.g., heat shock, ischemia and hemodynamics) produce multiple changes in a cell that affect metabolic processes and cellular structures. In response, stress proteins are synthesized, and are thought to mediate cytoprotection through biological function as molecular chaperones. Accumulated evidence indicates that HSP70, HSP90, HSP47, HSP32 and HSP27 play an important role during cardiac ischemia, ischemia preconditioning, cardiac hypertrophy and vascular wall injury.
 ...
PMID:[Progress in research on heat shock proteins in cardiovascular system]. 1265 63


<< Previous 1 2 3 4 5 6 Next >>