Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid rafts represent a subcompartment of the plasma membrane that coordinate and regulate varieties of signaling processes while caveolins are the integral membrane protein of the lipid raft. To study the role of lipid raft in ischemic preconditioning (PC) of the heart, rat hearts were perfused by working mode and then preconditioned in absence or presence of a lipid raft disintegrator, Methyl-beta-cyclodextrin. As expected, precondition made the heart resistant to ischemia reperfusion (I/R) injury as evident by improved ventricular performance, reduced myocardial infract size and cardiomyocyte apoptosis. Cyclodextrin abolished the cardioprotection. Transmission Electron Microscopy revealed severe degeneration, swelling of mitochondria, chromatin condensation and myofibril disarray in cyclodextrin treated PC heart similar to I/R heart. In the PC hearts, there was an increased association of the proapoptotic p38MAPKalpha with caveolin-1 while there was a reduced association of anti-apoptotic p38MAPKbeta with caveolin-3 indicating that reduced amount of p38MAPKalpha and increased amount of p38MAPKbeta were available to the adapted hearts thereby generating a survival signal. In contrast, there was very weak caveolin-MAP kinase interaction in cyclodextrin treated heart. Myocardial damage was further confirmed by reduced or no expression of anti-apoptotic phospho-AKT, Bcl2, Bcl-xl and increased expression of pro-apoptotic JNK, BAX, and p53 in methyl-beta-cyclodextrin (lipid raft disintegrator) treated heart. These results indicate that lipid raft play a pivotal role in the generation of survival signal in PC or adapted heart and disintegration of lipid raft completely abolish cardioprotection.
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PMID:Essential role of lipid raft in ischemic preconditioning. 1844 21

Since the generation of nitric oxide (NO) is an essential step in the trigger phase of ischemic preconditioning, short-term inhalation of NO before ischemia should ameliorate ischemia/reperfusion (I/R) injury of the lung. We tested this hypothesis in high oxygen (>99%) ventilated rats in order to additionally evaluate compatibility of NO and exposure to hyperoxia. Male adult Sprague-Dawley rats inhaled NO (15 ppm, 10 min) before the left lung hilum was clamped for 1 h, and the reperfusion phase was observed for 4 h (NO group). Animals in the I/R group underwent the same treatment, but without NO inhalation. A third group without I/R served as time-matched controls. Animals in the I/R group showed severe I/R injury in terms of arterial pO2 (apO2), which was reduced to 22% of surgical controls (SCs) at time point 30 min reperfusion, and increased endothelial permeability (Evans blue procedure). The pretreatment with NO attenuated these effects. The pO2 after 4 h reperfusion was still 3.0-fold higher in the NO group compared to I/R. In contrast, the I/R- and hyperoxia-induced invasion of leukocytes, as determined by measuring myeloperoxidase (MPO) activity, was not affected by NO. These data were correlated with the activity of major cellular signaling pathways by measuring the phosphorylation at activating and inhibitory sites of extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, protein kinase B (AKT), and glycogen synthase kinase 3beta (GSK-3beta), and by determination of cGMP in plasma and lung tissue. Inhalation of NO partly prevented the loss of activation by I/R and hyperoxic ventilation of ERK, JNK, and AKT, and it reduced the I/R-induced activation of GSK-3beta. The level of cGMP in plasma and lung tissue was increased in the NO group after 4 h reperfusion. In conclusion, application of inhaled NO in the preconditioning mode prevented I/R injury in the rat lung without interfering effects of hyperoxic ventilation. The effects of NO on cellular signaling pathways resemble mechanisms of ischemic preconditioning, but further studies have to evaluate the physiological relevance of these results.
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PMID:Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs. 1845 45

Heat stress (HS)-induced cardioprotection is associated with increased paxillin localization to the membrane fraction of neonatal rat ventricular myocytes (NRVM). The purpose of this study was 1) to examine the subcellular signaling pathways activated by HS; 2) to determine whether myocardial stress organizes and activates an integrated survival pathway; and 3) to investigate potential downstream cytoprotective proteins activated by HS. After HS, NRVM were subjected to chemical inhibitors (CI) designed to simulate ischemia by inhibiting both glycolysis and mitochondrial respiration. Protein kinase B (AKT) expression (wild type) was increased selectively with an adenoviral vector. Cell signaling was analyzed with Western blot analysis, while oncosis/apoptosis was assayed by measuring Trypan blue exclusion and/or terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. HS increased phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 but did not adversely affect the viability of NRVM before CI. HS increased association between FAK and phosphatidylinositol 3-kinase as well as causing a significant increase in AKT activity. Increased expression of wild-type AKT protected myocytes from both oncotic and apoptotic cell death. Increased expression of a FAK inhibitor, FRNK, reduced AKT phosphorylation in response to HS both at time 0 and after 10 min of CI compared with myocytes expressing empty virus. We conclude that myocardial stress activates cytoskeleton-based signaling pathways that are associated with protection from lethal cell injury.
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PMID:Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes. 1853 55

Recent studies on the protection afforded by moderate wine consumption against cardiovascular diseases have focused mainly on the activity of red wine in view of its high content of antioxidants, especially polyphenols. White wine lacks polyphenols, but it contains other compounds such as hydroxycinnamic acids (caffeic acid) and monophenols (tyrosol), which are known to have antioxidant properties. Therefore, this study was designed to examine the effect of white wine in myocardial ischemic-reperfusion injury. The experimental rats were gavaged with white wine (Soave Suavia "Le Rive" 2004) at a dosage of 6.5 mL/(kg.rat.day) for 30 days. Rats were divided into four groups: control sham (CS), wine-treated sham (WS), control ischemia (I)/reperfusion (R) (CIR), and wine + IR (WIR). All the rats in both IR groups underwent 30 min occlusion of the left anterior descending coronary artery followed by 8, 24 h, and 30 days of reperfusion (R). Significant reduction in infarct size (21 vs 39%, n = 6), cardiomyocyte (274 vs 384 counts/100 HPF, n = 6), and endothelial cell apoptosis (387 vs 587 counts/100 HPF) was observed in WIR as compared with CIR after 24 h of reperfusion. Echocardiography demonstrated significant increased fractional shortening (32 vs 22%) and ejection fraction (60 vs 44%) following 30 days of reperfusion in WIR rats compared to CIR ( n = 6). In addition, increased phosphorylation of AKT, Foxo3a, and eNOS were found in WS and WIR, as compared to their respective controls. The gel-shift analysis demonstrated significant upregulation of DNA binding activity of NF-kappaB in the white wine-treated groups. This report demonstrated for the first time that the white wine mediated cardioprotection in ischemic reperfused myocardium is through the PI-3kinase/Akt/FOXO3a/e-NOS/NF-kappaB survival pathway.
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PMID:White wine induced cardioprotection against ischemia-reperfusion injury is mediated by life extending Akt/FOXO3a/NFkappaB survival pathway. 1864 40

Both sphingosine and sphingosine-1-phosphate (S1P) were able to protect the ex vivo rat heart from ischemia reperfusion injury when added to the perfusion medium at the time of reperfusion after a 40min ischemia (postconditioning). Inhibitor studies revealed distinct mechanisms of protection, with S1P employing a G-protein coupled receptor pathway and sphingosine a cyclic nucleotide dependent protein kinase pathway. However, both restored ischemia-induced depletion of phospho-AKT. Extending the ischemia to 75min reduced protection by both S1P and sphingosine, but protection could be enhanced by employing them in combination. Extending the time of ischemia further to 90min almost eliminated cardioprotection by S1P or sphingosine; and their combination gave only modest protection. However, when S1P plus sphingosine was combined with a novel ramped ischemic postconditioning regimen, left ventricle developed pressure recovered by 66% and there was only a 6% infarct size. The data indicate that detrimental changes are accumulating during protracted ischemia but for up to 90min this damage is not irreversible and hearts can still recover with proper treatment.
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PMID:Combined sphingosine, S1P and ischemic postconditioning rescue the heart after protracted ischemia. 1870 87

PTEN is a dual lipid and protein phosphatase that antagonizes PI3K as well as other signaling pathways and regulates cellular survival and growth. However, its potential role in cardiac ischemia/reperfusion injury remains unknown. We established a transgenic mouse model with inducible and cardiac specific deletion of Pten gene (Pten(CKO)) in adult heart via tamoxifen dependent Cre-loxP mediated DNA recombination. 3 weeks after tamoxifen induced PTEN inactivation, elevated PI3K activity was observed in the Pten(CKO) hearts as determined from downstream AKT signaling. No significant differences in cardiac function as well as chamber size were observed between Pten(CKO) and Control animals based on echocardiography. In response to 30 min ischemia followed by 120 min reperfusion in Langendorff preparations, Pten(CKO) hearts developed significantly better function recovery than Control animals. At 60 min post reperfusion, the recovery of LVDP reached 77.9% of pre-ischemia basal in Pten(CKO) hearts vs 44.2% of Control (p<0.01). Consistent with the observed functional improvement, TTC staining revealed a significant reduction in infarct size in Pten(CKO) hearts compared with Control (24.2% vs 39.7%, p<0.05). Pten(CKO) hearts had significantly fewer apoptosis positive cardiomyocytes after I/R injury as identified by TUNEL staining. Furthermore, ERK activity and BCL-2 expression were not affected at basal but became significantly higher after ischemia/reperfusion in Pten(CKO) hearts. These data indicate that PTEN may play a role in ischemia/reperfusion injury by inhibiting anti-apoptotic survival signals. Inhibiting PTEN may serve as a potential approach to exert cardiac protection against ischemia reperfusion injury.
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PMID:Inducible and cardiac specific PTEN inactivation protects ischemia/reperfusion injury. 1903 62

Ischemic postconditioning (IPoC) reduces infarct size following ischemia/reperfusion. Whether or not phosphorylation of RISK (reperfusion injury salvage kinases) (AKT, ERK1/2, P70S6K, GSK3beta) is causal for protection by IPoC is controversial. We therefore studied the impact of RISK on IPoC in anesthetized pigs subjected to 90 minutes of left anterior descending coronary artery hypoperfusion and 120 minutes of reperfusion. In protocol 1, IPoC, by 6 cycles of 20/20 seconds of reperfusion/reocclusion (n=13), was compared with immediate full reperfusion (IFR) (n=15). In protocol 2, IPoC (n=4) or IFR (n=4) was performed with pharmacological RISK blockade by IC coinfusion of Wortmannin and U0126. Infarct size was determined by TTC staining, and the expression of phosphorylated RISK proteins by Western blot analysis in biopsies. In protocol 1, infarct size was 20+/-3% (percentage of area at risk; mean+/-SEM) with IPoC and 33+/-4% (P<0.05) with IFR. RISK phosphorylation increased with reperfusion but was not different between IPoC and IFR. In protocol 2, Wortmannin and U0126 blocked the increases in RISK phosphorylation during reperfusion, but infarct size was still smaller with IPoC (15+/-7%) than with IFR (35+/-6%; P<0.05).
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PMID:Ischemic postconditioning in pigs: no causal role for RISK activation. 1903 64

Potent endogenous protection from ischemia can be induced in the retina by ischemic preconditioning (IPC). Protein kinase B/Akt is a cellular survival factor. We hypothesized that Akt was integral to IPC based upon differential effects of Akt subtypes. Rats were subjected to retinal ischemia after IPC or IPC-mimicking by the opening of mitochondrial KATP (mKATP) channels. The effects of blocking Akt using wortmannin, API-2, or small interfering RNA (siRNA) were examined. Electroretinography assessed functional recovery after ischemia, and TUNEL examined retinal ganglion cell apoptosis. We studied the relationship between Akt activation and known initiators of IPC, including adenosine receptor stimulation and the opening of mKATP channels. The PI-3 kinase inhibitor wortmannin 1 or 4 mg/kg (i.p.), the specific Akt inhibitor API-2, 5-500 microM in the vitreous, or intravitreal siRNA directed against Akt2 or -3, but not Akt1, significantly attenuated the neuroprotective effect of IPC. Interfering RNA against any of the three Akt subtypes significantly but time-dependently attenuated mKATP channel opening to mimic IPC. Adenosine A1 receptor blockade (DPCPX), A2a blockade (CSC), or the mKATP channel blocker 5-hydroxydecanoic acid significantly attenuated Akt activation after IPC. Interfering RNA directed against Akt subtypes prevented the ameliorative effect of IPC on post-ischemic apoptosis. All three Akt subtypes are involved in functional retinal neuroprotection by IPC or IPC-mimicking. Akt is downstream of adenosine A1 and A2a receptors and mKATP channel opening. The results indicate the presence in the retina of robust and redundant endogenous neuroprotection based upon subtypes of Akt.
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PMID:The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning. 1908 3

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed hydroxy radical scavaging agent which has been widely used for protection against ischemia-reperfusion injury is highly effective in preventing cell apoptosis. However, the exact intracellular mechanism(s) underlying the protective action of edaravone is not clear. We observed that in PC12 cells cultured under serum deprivation (DEPV) condition, the levels of survivin were positively correlated with the anti-apoptotic action of edaravone. Survivin RNA interference (RNAi) increased DEPV-induced PC12 cell apoptosis, whereas the anti-apoptotic effect of edaravone was blunted by survivin RNAi. Moreover, survivin overexpression provided protection against DEPV-induced PC12 cell apoptosis. Inhibition of ERK and PI(3)-K/AKT prevented edaravone's ability to decrease apoptosis and increase survivin. In conclusion, the present study provides the first direct evidence that survivin involves in the anti-apoptotic effects of edaravone via a pathway involving ERK and PI(3)-K/AKT.
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PMID:Survivin is involved in the anti-apoptotic effect of edaravone in PC12 cells. 1922 41

The transcription factor STAT1 plays a role in promoting apoptotic cell death, whereas the related STAT3 transcription factor protects cardiac myocytes from ischemia/reperfusion (I/R) injury or oxidative stress. Cytokines belonging to the IL-6 family activate the JAK-STAT3 pathway, but also activate other cytoprotective pathways such as the MAPK-ERK or the PI3-AKT pathway. It is therefore unclear whether STAT3 is the only cytoprotective mediator against oxidative stress-induced cell death. Overexpression of STAT3 in primary neonatal rat ventricular myocytes (NRVM) protects against I/R-induced cell death. Moreover, a dominant negative STAT3 adenovirus (Ad ST3-DN) enhanced apoptotic cell death (81.2+/-6.9%) compared to control infected NRVM (46.0+/-3.1%) following I/R. Depletion of STAT3 sensitized cells to apoptotic cell death following oxidative stress. These results provide direct evidence for the role of STAT3 as a cytoprotective transcription factor in cells exposed to oxidative stress.
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PMID:STAT3 deletion sensitizes cells to oxidative stress. 1945 May 59


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