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)

Because tyrosine kinase blockade prevents protection by ischemic preconditioning (p.c.) in several species, activation of tyrosine kinase appears to be critical for cardioprotection. The tyrosine kinase's identity, however, is unknown. The present study tested whether activation of a receptor tyrosine kinase, the insulin receptor, could mimic p.c. and if the mechanism of protection was similar to that of p.c. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarct size in control hearts was 32.6 +/- 2.3%. A 5-min infusion of insulin (5 mU/ml) followed by a 10-min washout period prior to ischemia significantly reduced infarction to 14.7 +/- 2.1% (P < 0.05). The tyrosine kinase inhibitor genistein (50 microM) given around the insulin infusion blocked protection (28.9 +/- 2.8%). However, when present during the onset of ischemia, genistein had no effect on protection triggered by insulin (14.0 +/- 2.4%; P < 0.05). Inhibition of either PKC by polymyxin B (50 microM) or KATP channels by 5-hydroxydecanoate (100 microM) also failed to prevent protection by insulin (17.5 +/- 3.2% and 17.6 +/- 3.0%, respectively). However, the reduction in infarct size by insulin was significantly attenuated by wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K, 28.3 +/- 2.2%). Insulin was still able to protect the heart when given only during the reperfusion period (13.2 +/- 3.4%). P.c. reduced infarction to 12.8 +/- 2.0% (P < 0.05) and still offered significant protection in the presence of wortmannin (22.1 +/- 2.4%; P < 0.05). In conclusion, activation of the insulin receptor reduces infarct size in the rabbit heart even when instituted upon reperfusion. However, the mechanism of protection is quite different from that of p.c. and involves activation of PI3K but not PKC or KATP channels.
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PMID:Myocardial protection by insulin is dependent on phospatidylinositol 3-kinase but not protein kinase C or KATP channels in the isolated rabbit heart. 1042 37

A phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor gene that suppresses cell growth, inhibits cell migration, and induces apoptosis. Phosphorylated form of PTEN (p-PTEN) is a key survival factor relating PI3K-Akt pathway and their downstream effectors. A spatiotemporal profiles of PTEN and p-PTEN expression were immunohistochemically examined after 90 min of transient middle cerebral artery occlusion in rats. In the ischemic core, PTEN progressively decreased by 3 days, whereas a rapid but transient increase of p-PTEN was found with a peak at 1 h after the reperfusion. In contrast, in the ischemic penumbra, PTEN showed a minor change and a gradual but sustained p-PTEN expression was observed in the ischemic penumbra with a peak at 12 h. In addition, the balance of population among strongly, moderately, and weakly stained cells was different between the ischemic core and penumbra at their peak time points. These results suggest an important role of p-PTEN for cell survival after ischemia as an upstream regulator for PI3K-Akt.
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PMID:Enhanced phosphorylation of PTEN in rat brain after transient middle cerebral artery occlusion. 1241 16

Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been shown to be elevated in the serum of patients with ischemic heart disease and valvular heart disease, and induces cardiomyocyte hypertrophy in vitro. We investigated expression of CT-1 in post-MI rat heart and the effect of CT-1 on cultured primary adult rat cardiac fibroblasts. Elevated CT-1 expression was observed in the infarct zone at 24 h and continued through 2, 4 and 8 weeks post-MI, compared to sham-operated animals. CT-1 induced rapid phosphorylation of Jak, Jak2, STAT1, STAT3, p42/44 MAPK and Akt in cultured adult cardiac fibroblasts. CT-1 induced cardiac fibroblast protein synthesis and proliferation. Protein and DNA synthesis were dependent on activation of Jak/STAT, MEK1/2, PI3K and Src pathways as evidenced by decreased 3H-leucine and 3H-thymidine incorporation after pretreatment with AG490, PD98059, LY294002 and genistein respectively. Furthermore, CT-1 treatment increased procollagen-1-carboxypropeptide (PICP) synthesis, a marker of mature collagen synthesis. CT-1 induced cell migration of rat cardiac fibroblasts. Our results suggest that CT-1, as expressed in post-MI heart, may play an important role in infarct scar formation and ongoing remodeling of the scar. CT-1 was able to initiate each of the processes considered important in the formation of infarct scar including cardiac fibroblast migration as well as fibroblast proliferation and collagen synthesis. Further work is required to determine factors that induce CT-1 expression and interplay with other mediators of cardiac infarct wound healing in the setting of acute cardiac ischemia and chronic post-MI heart failure.
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PMID:Cardiotrophin-1: expression in experimental myocardial infarction and potential role in post-MI wound healing. 1467 4

High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1-50 microM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-kappa B translocation reversed heme antiapoptotic effect. NF-kappa B (p65 subunit) nuclear translocation and I kappa B degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.
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PMID:Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide 3-kinase, MAPK, and NF-kappaB. 1526 37

Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified gamma-amino butyric acid (GABA) type B receptor 2 (GABA(B)R2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABA(B)R2 demonstrated Akt association with the intact GABA(B)R. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABA(B)R2 Ab. Additionally, GABA(B)R2 and Akt colocalization was demonstrated by confocal microscopy. A GABA(B)R agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABA(B)R antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABA(B)R agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABA(B)R with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABA(B)R2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABA(B)R is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABA(B)R potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.
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PMID:Gamma-amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion. 1590 70

Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt-Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt-Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate-1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt-Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive.
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PMID:PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. 1607 47

Current studies demonstrated that cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. In our present work, the relationship between Akt1 and JNK1/2 was evaluated after cerebral ischemia-reperfusion in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. This paper was based on our present and previous studies. Firstly, Akt1 had one active peak during reperfusion following 15 min ischemia. Secondly, two peaks of JNK1/2 activation occurred during reperfusion, respectively. Thirdly, the phosphorylation of JNK substrates c-Jun and Bcl-2, and the activation of a key protease of caspase-3 were detected. They only had one active peak, respectively, during reperfusion. To clarify the mechanism of Akt1 activation and further define whether JNK1/2 activation could be regulated by Akt1 through PI3K pathway, LY294002 and insulin were, respectively, administrated to the rats prior to ischemia. Our research indicated that LY294002, a PI3K inhibitor, significantly suppressed Akt1 activation. Furthermore, LY294002 significantly strengthened both peaks of JNK1/2 activation, c-Jun activation, Bcl-2 phosphorylation, and the activation of caspase-3 during reperfusion. In contrast, insulin, a PI3K agonist, not only obviously activated Akt1 during early and later reperfusion, but also inhibited phosphorylation of JNK1/2, c-Jun, and Bcl-2 and attenuated the activation of caspase-3. In addition, pretreatment of insulin significantly increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion. Consequently, our results indicated that the cross-talk between Akt1 and JNK1/2 could be mediated by insulin receptor through PI3K in rat hippocampus during reperfusion. This signaling pathway might play a neuroprotective role against ischemic insults via inhibition of the JNK pathway, involving the death effector of caspase-3.
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PMID:The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation. 1601 89

Endothelial cells can protect cardiomyocytes from injury, but the mechanism of this protection is incompletely described. Here we demonstrate that protection of cardiomyocytes by endothelial cells occurs through PDGF-BB signaling. PDGF-BB induced cardiomyocyte Akt phosphorylation in a time- and dose-dependent manner and prevented apoptosis via PI3K/Akt signaling. Using injectable self-assembling peptide nanofibers, which bound PDGF-BB in vitro, sustained delivery of PDGF-BB to the myocardium at the injected sites for 14 days was achieved. A blinded and randomized study in 96 rats showed that injecting nanofibers with PDGF-BB, but not nanofibers or PDGF-BB alone, decreased cardiomyocyte death and preserved systolic function after myocardial infarction. A separate blinded and randomized study in 52 rats showed that PDGF-BB delivered with nanofibers decreased infarct size after ischemia/reperfusion. PDGF-BB with nanofibers induced PDGFR-beta and Akt phosphorylation in cardiomyocytes in vivo. These data demonstrate that endothelial cells protect cardiomyocytes via PDGF-BB signaling and that this in vitro finding can be translated into an effective in vivo method of protecting myocardium after infarction. Furthermore, this study shows that injectable nanofibers allow precise and sustained delivery of proteins to the myocardium with potential therapeutic benefits.
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PMID:Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. 1635 43

It has been well established that erythropoietin (EPO) can limit myocardial ischemia/reperfusion injury in a variety of acute settings. However, despite EPO being used chronically to treat anemia the infarct limiting effects of long term treatment (chronic) have never been fully investigated. In this study we examined the effects of a 3 week treatment of EPO (5,000 IU/Kg) in male Sprague Dawley rats in limiting myocardial infarction after 35 min ischemia and 2 h reperfusion in an in vitro isolated heart perfusion model. Treating the animals 'once a week' failed to limit infarct size significantly compared to a saline control (54.1% +/- 3.5 v 52.3% +/- 4.4), whereas a '3 times a week' regime succeeded in significantly reducing infarct size (36.2% +/- 3.2 v 52.3% +/- 4.4, p < 0.05). To demonstrate that the effect was not due to improved oxygen supply caused by a raised hematocrit level, we also administered EPO 24 h prior to ischemia/reperfusion. This treatment again reduced infarct size compared to a saline control (39.9% +/- 4.4 v 58.4% +/- 5.0, p < 0.05). To examine the mechanism of protection we used the PI3K inhibitor wortmannin and the nitric oxide synthase inhibitor L-NAME to try to abrogate EPO mediated protection. Where wortmannin failed to block the effects of EPO (31.7% +/- 6.0 v 36.2% +/- 3.2), L-NAME did abrogate protection (51.6% +/- 5.6 v 36.2% +/- 3.2, p < 0.05). We demonstrate that chronic EPO treatment limits infarct size and that it does so in a nitric oxide dependent manner.
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PMID:Chronic erythropoietin treatment limits infarct-size in the myocardium in vitro. 1638 95

Despite nearly twenty years of research into the field of ischemic preconditioning, the actual mechanism of protection remains unclear. However, much progress has been made in elucidating the signal transduction pathways that convey the extracellular signal initiated by the preconditioning stimulus to the intracellular targets of cardioprotection, with many of these pathways involving the activation of a diverse array of survival protein kinase cascades. The powerful protective benefits of ischemic preconditioning have not yet been realised in the clinical arena, not least because of the prerequisite for any preconditioning intervention to be applied prior to the onset of index ischemia, which in the case of an acute myocardial infarction is difficult to institute. In this regard, the newly described phenomenon of ischemic postconditioning, which comprises a cardioprotective intervention that can be applied at the time of myocardial reperfusion, offers a far more attractive and amenable approach to myocardial protection. Interestingly, certain survival protein kinase cascades recruited at the time of myocardial reperfusion appear to be shared by both ischemic preconditioning and postconditioning, thereby offering a potentially common target of cardioprotection. The often disputed roles these different protein kinases play in mediating the cardioprotective effects of ischemic preconditioning and postconditioning are reviewed in this article, and include protein kinases C, G, and A, members of the MAPK family (Erk1/2, p38, JNK and BMK1), the PI3K-Akt cascade, and the JAK-STAT pathway.
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PMID:Survival kinases in ischemic preconditioning and postconditioning. 1654 52


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