UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (gamma and delta) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K gamma/delta inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period.
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PMID:Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. 1717 49

The present study has been designed to pharmacologically investigate the role of phosphoinositide 3-kinase in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion-induced behavioral dysfunction in mice. Bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in mice. Short-term memory was evaluated using the elevated plus maze test. The inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced impaired short-term memory, motor co-ordination and lateral push response. Three episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced behavioral deficit measured in terms of loss of short-term memory, motor coordination and lateral push response. Wortmannin (2 mg/kg, iv), a phosphoinositide 3-kinase inhibitor given 10 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that beneficial effects of ischemic postconditioning on global cerebral ischemia and reperfusion-induced behavioral deficits may involve activation of phosphoinositide 3-kinase-linked pathway.
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PMID:Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice. 1755 97

Cerebral ischemia increases neural progenitor cell proliferation and neurogenesis. However, the precise molecular mechanism is poorly understood. The present study was undertaken to determine roles of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt and their signaling pathways in neural progenitor cells exposed to hypoxia/reoxygenation (H/R), an in vitro model of ischemia/reperfusion. Neural progenitor cells were isolated from postnatal mouse brain. ERK and Akt were transiently activated during the early phase of reoxygenation following 4-h of hypoxia. The ERK activation was inhibited by U0126, a specific inhibitor of MEK, but not by LY294002, a specific inhibitor of PI3K, whereas the Akt activation was blocked by LY294002, but not by U0126. Reoxygenation following 4-h hypoxia stimulated cell proliferation, which was dependent on ERK and Akt activation. Inhibitors of growth factor receptor (AG1478) and Src (PP2) and the antioxidant N-acetylcysteine did not affect activation of ERK and Akt, while the Ras and Raf inhibitors inhibited activation of ERK, but not Akt. PKC inhibitors inhibited both ERK and Akt activation. Taken together, these results suggest that H/R induces activation of MEK/ERK and PI3K/Akt survival signaling pathways through a PKC-dependent mechanism. These pathways may be responsible for the repair process during ischemia/reperfusion.
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PMID:Hypoxia/reoxygenation stimulates proliferation through PKC-dependent activation of ERK and Akt in mouse neural progenitor cells. 1756 63

We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3beta, an Akt effector. In addition, postconditioning blocked beta-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active beta-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting deltaPKC cleavage and attenuated reduction in phosphorylation of survival-promoting epsilonPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning's protection; furthermore, increases in epsilonPKC activity, a survival-promoting pathway, and reductions in MAPK and deltaPKC activity; two putative death-promoting pathways correlate with postconditioning's protection.
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PMID:The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. 1818 53

Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
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PMID:Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential. 1902 19

Thioredoxin (Trx) is a 12-kDa protein ubiquitously expressed in all living cells that fulfills a variety of biological functions related to cell proliferation and apoptosis. It is characterized by the highly conserved reduction/oxidation (redox)-active site sequence Trp-Cys-Gly-Pro-Cys-Lys. Trx acts as a powerful antioxidant and plays an important role in maintaining critical protein thiols in the reduced state. Moreover, it has been shown to scavenge reactive oxygen species (ROS) and to protect against oxidative stress. We have reported that Trx-1 protects against neuronal damage during focal ischemia. However, the mechanisms underlying this protective effect and the effect of Trx-1 on neuronal apoptosis during ischemia have not been fully clarified. In this study, we analyzed the effect of Trx-1 overexpression against neuronal degeneration after a short duration of transient brain ischemia. Mild focal ischemia was reported to induce neuronal death through apoptosis. We employed Fluorojade-B staining to detect neuronal degeneration. In Trx transgenic mice, a smaller number of Fluorojade-B-positive neurons were detected after ischemia-reperfusion than in wild-type mice. In addition, we detected cleaved caspase-3- and TUNEL-positive cells, which indicated caspase-dependent apoptosis. Fewer caspase-3- and TUNEL-positive neurons were detected after ischemia-reperfusion in Trx transgenic mice than in wild-type mice. Furthermore, Akt signaling was reported to play a role in neuronal survival in Trx-1 overexpressing mice. After ischemia-reperfusion, Western blot and immunohistochemical analysis indicated that phosphorylation of Akt was enhanced in Trx transgenic mice after ischemia-reperfusion. Intraventricular injection of LY294002,which is a phosphoinositide 3-kinase (PI3K), vanished the neuroprotective effect in Trx-1 transgenic mice. These results indicate that Trx-1 overexpression protects neurons from apoptosis after ischemia-reperfusion.
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PMID:Attenuation of neuronal degeneration in thioredoxin-1 overexpressing mice after mild focal ischemia. 1932 86

Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
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PMID:An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. 1940 99

Multiple signaling pathways via insulin receptor substrate-1 and -2 play crucial roles in health, diseases, and therapeutics (i.e., longevity, tumorigenesis, and neuroprotection). The 90-kDa heat-shock protein (Hsp90) is an emerging target molecule of therapeutics, Hsp90 inhibitors being promising against various diseases (e.g., cancer, brain and cardiac ischemia, and neurodegenerative diseases). Much remains, however, unknown whether Hsp90 could regulate insulin receptor substrate-1 and -2 signaling pathways. In cultured bovine adrenal chromaffin cells, we observed that 24-h treatment with 1 microM geldanamycin (an inhibitor of Hsp90) decreased insulin receptor substrate-1 level, while increasing insulin receptor substrate-2 level; besides, geldanamycin lowered phosphoinositide 3-kinase, phosphoinositide-dependent kinase-1, Akt, glycogen synthase kinase-3beta, and Raf-1 levels, without changing extracellular signal-regulated kinase and its upstream kinase levels. Chronic (>or=12h) treatment with 0.1-10 microM Hsp90 inhibitor (geldanamycin, 17-allylamino-17-demethoxy-geldanamycin, herbimycin A, and radicicol) decreased insulin receptor substrate-1 level by approximately 66%, while increasing insulin receptor substrate-2 level by approximately 160%. These effects of geldanamycin (IC(50) 155 nM, EC(50) 177 nM) and 17-allylamino-17-demethoxy-geldanamycin (IC(50) 310 nM, EC(50) 260 nM) were time- and concentration-dependent. Geldanamycin-induced decrease of insulin receptor substrate-1 was attenuated by lactacystin, beta-lactone or MG132 (proteasome inhibitor), but not by calpastatin (calpain inhibitor) or leupeptin (lysosome inhibitor); geldanamycin did not affect heteroprotein complex formation between insulin receptor substrate-1 or -2 and Hsp90. Geldanamycin-induced increase of insulin receptor substrate-2 was prevented by cycloheximide or actinomycin D. Geldanamycin lowered insulin receptor substrate-1 mRNA level by approximately 39%, while raising insulin receptor substrate-2 mRNA level by approximately 109% between 3 and 24h, without changing the stability of insulin receptor substrate-1 and -2 mRNAs. Nuclear run-on assay revealed that geldanamycin retarded insulin receptor substrate-1 gene transcription by 42%, while accelerating insulin receptor substrate-2 gene transcription by 41%. Hsp90 inhibitors oppositely altered insulin receptor substrate-1 and -2 levels via proteasomal degradation and gene transcription.
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PMID:Distinct regulation of insulin receptor substrate-1 and -2 by 90-kDa heat-shock protein in adrenal chromaffin cells. 1973 90

We evaluated the cardioprotection against myocardial ischemia-reperfusion injury induced by sevoflurane postconditioning (SpostC) in chronically-infarcted rat hearts, and investigated the roles of phosphoinositide 3-kinase (PI3K)-protein kinase B/Akt (PKB/Akt), mitogen-activated extracellular regulated kinase 1/2 (MEK 1/2)-extracellular regulated kinase 1/2 (ERK 1/2), and mitochondrial permeability transition pore (mPTP). Left anterior descending (LAD) coronary artery was ligated to induce myocardial infarction in rats. Six weeks later, chronically-infarcted hearts were isolated and subjected to 30 min of global ischemia, followed by 1 h of reperfusion with Krebs-Henseleit (K-H) buffer. SpostC was administered by perfusing the hearts with K-H buffer saturated with 3% sevoflurane during the first 15 min of reperfusion. To evaluate the role of PI3K-PKB/Akt and MEK 1/2-ERK 1/2 in SpostC, PI3K inhibitor LY294002 (15 microM) and MEK 1/2 inhibitor PD98059 (20 microM) were administered alone or together with sevoflurane during the first 15 min of reperfusion. We found that exposure of 3% sevoflurane during early reperfusion significantly improved functional recovery (improved left ventricular developed pressure (LVDP), +/-dp/dt, CF, HR and reduced left ventricular end-diastolic pressure (LVEDP)), decreased myocardial infarct size and reduced LDH and CK-MB release, when compared with unprotected hearts. However, these protective effects were abolished in the presence of either LY294002 or PD98059, which was accompanied by the prevention of PKB/Akt and ERK 1/2 phosphorylation, and reduction of myocardial nicotinamide adenine dinucleotide (NAD+) content. These findings suggest that sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by inhibiting mPTP opening via recruitment of PKB/Akt and ERK 1/2.
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PMID:Sevoflurane postconditioning protects chronically-infarcted rat hearts against ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability transition pore opening upon reperfusion. 1988 Dec 97

Parstatin, the N-terminal 41-amino-acid peptide cleaved by thrombin from the protease-activated receptor 1, protects against rat myocardial ischemia and reperfusion injury. In this study, we determined that the parstatin fragment 1-26, the putative signal peptide of protease-activated receptor 1, contains the functional domain of parstatin. We assessed a synthesized parstatin(1-26) peptide in an in vivo rat model of myocardial regional ischemia-reperfusion injury (n = 6/group). Infarct size in control rat hearts was 58 +/- 1% area at risk. Parstatin(1-26) was able to reduce infarct size to 13 +/- 1% (P < 0.001) and 22 +/- 1% area at risk (P < 0.01) when given before or after reperfusion. The infarct-sparing effects of parstatin(1-26) were abolished by inhibition of G(i) proteins (pertussis toxin), phosphoinositide 3-kinase/Akt (wortmannin), nitric-oxide synthase (NOS; N(G)-monomethyl-l-arginine), soluble guanylyl cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], and sarcolemmal and mitochondrial K(ATP) channels [glibenclamide, 5-hydroxydecanoic acid, and sodium (5-(2-(5-chloro-2-methoxybenzamido)ethyl)-2-methoxyphenylsulfonyl) (methylcarbamothioyl)amide (HMR 1098)]. Parstatin(1-26) cardioprotection was also abolished by atractyloside, a mitochondrial permeability transition pore (mPTP) opener. The inhibitors and opener alone had no effect on infarct size. Furthermore, preischemic treatment with parstatin(1-26) increased Akt and endothelial NOS phosphorylation at the time of reperfusion. After a 120-min reperfusion, parstatin(1-26) increased nitric oxide levels (12 +/- 0.4 to 17 +/- 0.9 mmol/g tissue) and cyclic GMP levels (87 +/- 21 to 395 +/- 36 pmol/g tissue). Parstatin(1-26) treatment either before or after ischemia results in an extremely efficacious protection against ischemia-reperfusion injury that depends on a G(i) protein-mediated pathway involving mPTP, the end effector of the preconditioning pathway. This suggests that parstatin(1-26) has a potential therapeutic role in the treatment of ischemia and reperfusion injury.
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PMID:Parstatin(1-26): the putative signal peptide of protease-activated receptor 1 confers potent protection from myocardial ischemia-reperfusion injury. 2000 57

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