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)

Fibroblasts possess receptors for compounds released during ischemia, including bradykinin. The aims of the present study were to investigate tyrosine kinase and p38 MAP kinase signalling in heart derived myofibroblasts in response to bradykinin and preconditioning ischemia. Fibroblasts from neonatal rat hearts were subjected to pharmacological agents and/or simulated ischemia. Cell viability was measured by the conversion of a tetrazolium salt to its formazan derivative. Preconditioning with 30 min of simulated ischemia followed by 30 min recovery resulted in an 85.4% +/- 7.8% increase in cell survival above that of cells treated with prolonged ischemia alone. Cells treated with bradykinin showed a 35% +/- 7.9 increase in cell survival after lethal ischemia. The B2 receptor antagonist Hoe 140 blocked the protective effect of bradykinin, but did not block preconditioning. The K(ATP) channel blocker glibenclamide and the mitochondria specific K(ATP) blocker 5, hydroxydecanoate, abolished the cytoprotection induced by both preconditioning and bradykinin. The non specific tyrosine kinase inhibitor genistein also abolished the cytoprotection. Effective blockade of cytoprotection was obtained with K(ATP) channel blockers and the tyrosine kinase inhibitor when these compounds were given prior to the preconditioning stimulus and not during the lethal insult. The stress activated protein kinase p38 MAP kinase was investigated by Western blotting and by the use of a specific inhibitor (SB203580). Preconditioning reduced phospho-p38 MAP kinase; in contrast, bradykinin administration markedly increased phosphorylation of p38 MAP kinase. SB203580 protected cells from lethal simulated ischemia. In conclusion, cell survival-signalling pathways activated by bradykinin or simulated ischemia in heart fibroblasts protect via the opening of K(ATP) channels and are independent of the stress-activated p38 MAP kinase and/or related to inhibition of this kinase.
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PMID:Cell survival signalling in heart derived myofibroblasts induced by preconditioning and bradykinin: the role of p38 MAP kinase. 1512 11

We investigated whether ischemic preconditioning (PC) attenuates ischemia/reperfusion-induced injury in part by decreasing apoptosis and whether tyrosine kinase (TK) can regulate the signaling pathway leading to apoptosis in delayed cardioprotection. Six groups of rabbits were studied in the early phase (EP) and in the delayed phase (DP): (1) sham-operated control animals were received vehicle only (Veh-sham); (2) rabbits that received I.V. genistein (a nonspecific TK inhibitor) 10 min before ischemia (Gen-sham); (3) rabbits that received I.V. daidzein (an inactive structural analog of genistein) 10 min before ischemia (Dzn-sham); (4) rabbits preconditioned with 4 cycles of 5-min occlusion of left anterior descending coronary artery (LAD) and 10-min reperfusion (PC); (5) rabbits that received I.V. genistein, 10 min before PC (Gen-PC); (6) rabbits that received I.V. daidzein 10 min before PC (Dzn-PC). All rabbits underwent 30-min ischemia followed by 180-min reperfusion. Infarct size in the PC, Gen-PC, and Dzn-PC groups in the EP was significantly (p < 0.0001) reduced relative to controls Gen and Dzn. Delayed cardioprotection was blocked significantly (p < 0.0001) by genistein. In the EP, apoptosis was significantly (p < 0.0001) decreased in PC, Gen-PC, and Dzn-PC groups relative to controls Gen and Dzn. In the DP, a reduction of apoptosis was not seen in the Gen-PC group. This study suggests that PC reduces ischemic injury in part by decreasing apoptosis after ischemia/reperfusion and also that TK phosphorylation is involved in the signal transduction cascade leading to the decline of apoptosis in the DP.
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PMID:Pretreatment with tyrosine kinase inhibitor attenuates the reduction of apoptosis 24 h after ischemic preconditioning. 1518 21

Vascular endothelial growth factor (VEGF) receptor-2 (KDR/flk-1) has a tyrosine kinase domain and, once activated, induces the autophosphorylation of the tyrosine residues. The phosphorylated KDR/flk-1 can be a substrate for intracellular protein tyrosine phosphatases (PTPs). In the present study, we have examined whether the PTP inhibitor sodium orthovanadate (SOV) activates KDR/flk-1 and accelerates angiogenesis in a rat model of hindlimb ischemia. The left femoral artery was exposed and excised to induce limb ischemia. The PTP activity in ischemic adductors increased, whereas SOV significantly suppressed the increase in the activity. Tyrosine phosphorylation of KDR/flk-1 and Akt phosphorylation significantly increased in the muscles injected with SOV compared with those injected with saline. The amount of VEGF increased in both the muscles injected with SOV and those injected with the saline but did not differ significantly. At 21 days after the induction of ischemia, immunohistochemical studies demonstrated that muscles injected with SOV showed significantly increased capillary density compared with those injected with saline. In a rat model of hindlimb ischemia, not only VEGF but also PTP, which might impair angiogenesis, increased. SOV activated KDR/flk-1 and accelerated angiogenesis. Thus, a PTP inhibitor can be a new drug for therapeutic angiogenesis in peripheral ischemic diseases.
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PMID:A protein tyrosine phosphatase inhibitor accelerates angiogenesis in a rat model of hindlimb ischemia. 1545 54

Epithelial injury and repair are central consequences of ischemia and reperfusion of the gut. Intestinal mucosal wounds are repaired in part by epithelial restitution. However, the signaling mechanisms regulating restitution remain poorly understood, and few therapies to enhance restitution have been described. Previously we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH) protected against postischemic gut injury in the rat. In this report, we tested the effects and mechanisms of alpha-MSH on wound restitution of rat small intestine (IEC-6) cells subjected to H2O2 stress with or without scrape wounding. H2O2 treatment resulted in tyrosine phosphorylation of Syk kinase and its downstream target IkappaBalpha, with subsequent NF-kappaB activation. Alpha-MSH and the Syk kinase inhibitor piceatannol blocked these processes. In scrape-wounded cells, H2O2 inhibited wound restitution, and this was partially restored by cotreatment with alpha-MSH or piceatannol. In contrast, overexpression of NF-kappaB p65 or Syk kinase, but not a dominant-negative mutant of Syk kinase, aggravated H2O2 inhibition of wound restitution, and inhibitors of c-Src tyrosine kinase or phosphatidylinositol-3 kinase were without effect. The results indicate an important role for Syk tyrosine kinase and the NF-kappaB pathway in the response to oxidant stress and the impairment of epithelial restitution in IEC-6 cells. The data also disclose that the beneficial effects of alpha-MSH on gut ischemia/reperfusion injury may relate to its acceleration of epithelial restitution.
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PMID:Alpha-melanocyte stimulating hormone protects against H2O2-induced inhibition of wound restitution in IEC-6 cells via a Syk kinase- and NF-kappabeta-dependent mechanism. 1548 38

Hepatocellular carcinoma is the fifth leading cause of cancer worldwide and its incidence is increasing. Surveillance programs allow doctors to identify patients at early stages of the disease, when the tumor may be curable by radical treatments such as resection, liver transplantation, or local ablation. In the West, these treatments can be applied to 30% to 40% of patients. Resection yields favorable results in patients with single tumors and a well-preserved liver function (5-year survival rate is 60%). Recurrence complicates two thirds of the cases, and there is no effective adjuvant treatment. Liver transplantation is the best treatment for patients with single tumors that are less than 5 cm in diameter and liver failure, or in those presenting with three nodules less than 3 cm, but organ shortage greatly limits its applicability. Long-term survival is expected to be around 50% to 70% at 5 years depending upon the drop-out rate of patients on the waiting list. Chemoembolization and local ablation are the neo-adjuvant treatments applied to patients on the waiting list to prevent tumor progression; no controlled study proving their efficacy has yet been published. In nonsurgical candidates, percutaneous treatments (ethanol injection or radiofrequency ablation) are the best therapeutic approach and improve survival in Child-Pugh A class patients with small tumors that achieve initial complete response (5-year survival rate is 40% to 50%). At more advanced stages, chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has shown to slightly improve survival in a meta-analysis of randomized trials. No survival advantages have been demonstrated with intra-arterial or systemic chemotherapy, hormonal compounds, or radiation. New agents, such as inhibitors of the tyrosine kinase receptors of growth factors and antiangiogenic agents, are currently being tested in phase II/III trials.
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PMID:Treatment of Hepatocellular Carcinoma. 1552 9

In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.
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PMID:The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. 1555 28

Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. However, other elements of the Met(5)-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca(2+)-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 microM) did not. Treatment with herbimycin (1 microM) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr(992) and Tyr(1068). Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 microM) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 microM), and chelerythrine (2 microM). The PI3K inhibitor LY-294002 (20 microM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser(473) was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.
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PMID:Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K. 1556 40

It is well established that brief episodes of ischemia/reperfusion (I/R) [preconditioning (PC)] protect the myocardium from the damage induced by subsequent more prolonged I/R. However, the signaling pathways activated during PC or I/R are not well characterized. In this study, the role of Ras-GTPase, tyrosine kinases (TKs), epidermal growth factor receptor (EGFR) and Ca2+/calmodulin-dependent protein kinase II (CaMK II) in mediating PC in a perfused rat heart model was investigated. A 40-min episode of global ischemia in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). PC significantly enhanced cardiac recovery after IR. Combination of PC and FPT III (Ras-GTPase inhibitor FPT III; 232 ng/min for 6 days) treatment did not produce any additive benefits as compared to PC alone. In contrast, PC-induced improvements in cardiac function after I/R were significantly attenuated by pretreatment with genistein (1mg/kg/day for 6 days), a broad-spectrum inhibitor of TKs, or AG1478 (1mg/kg/day for 6 days), a specific inhibitor of EGFR tyrosine kinase or KN-93 (578 ng/min for 6 days), a CaMK II inhibitor, before PC. These observations suggest that PC and FPT III pretreatment may produce cardioprotection via similar mechanisms. Present results also indicate that activation of TKs and specifically activation of EGFR-mediated TKs and CaMK II-mediated regulation of calcium homeostasis are part of the PC mechanisms that improve recovery after IR.
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PMID:Signal transduction mechanisms involved in cardiac preconditioning: role of Ras-GTPase, Ca2+/calmodulin-dependent protein kinase II and epidermal growth factor receptor. 1572 51

In the present study, ischemia-related changes in tyrosine kinase A (trkA) and phosphacan/protein tyrosine phosphatase-zeta/beta (PTP-zeta/beta) immunoreactivities and protein contents were examined in the hippocampus proper after transient forebrain ischemia for 5 min in a gerbil model. Our investigations showed that ischemia-induced changes occurred in trkA immunoreactivity in the hippocampal CA1 region, but not in the CA2/3 region of the hippocampus proper. In the sham-operated group, trkA immunoreactivity was barely detectable. trkA immunoreactivity increased from 30 min after ischemia and peaked at 12 h. Four days after ischemic insult, trkA immunoreactivity was observed in GFAP-immunoreactive astrocytes in the strata oriens and radiatum. In addition, we found that ischemia-related changes in trkA protein content were similar to immunohistochemical changes. On the other hand, PTP-zeta/beta immunoreactivities in the hippocampus proper were unaltered by forebrain ischemia. These results suggest that chronological changes of trkA after transient forebrain ischemia may be associated with an ischemic damage compensatory mechanism in CA1 pyramidal cells.
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PMID:Tyrosine kinase A but not phosphacan/protein tyrosine phosphatase-zeta/beta immunoreactivity and protein level changes in neurons and astrocytes in the gerbil hippocampus proper after transient forebrain ischemia. 1572 99

We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation.
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PMID:Somatostatin analogue mimics acute ischemic preconditioning in a rat model of myocardial infarction. 1577 21


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