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)

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.
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PMID:Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. 1132 78

We determined the role of p38 mitogen-activated protein kinase (MAPK), 72-kDa heat shock protein (HSP72), and antioxidant enzymes in whole body heat stress (HS)-induced cardioprotection in mouse hearts. Adult male mice were treated with either HS or anesthesia only. At 0.5, 48, 72, or 120 h later, the hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. A significant protection against ischemia-reperfusion injury was observed 48 h after HS as demonstrated by: 1) reduction in infarct size; 2) decrease in leakage of lactate dehydrogenase; and 3) enhanced postischemic ventricular contractile function. No such protection was observed at other post-HS time points. HS caused an ~25% increase in phosphorylated c-Jun NH2-terminal kinase (JNK) but not p38 MAPK in the heart during the first 2-h post-HS time period. Cardioprotection was abolished by the MAPK inhibitor SB-203580, which also partially suppressed the HS-induced JNK phosphorylation. The protective effect was associated with a two- to threefold increase in HSP72 protein accumulation, but not antioxidant enzyme activities (catalase and Cu/Zn and Mn SOD) in the myocardium. Although HSP72 levels remained high 72 h after HS, the cardioprotection had already disappeared. We conclude that HS induces a transient delayed cardioprotection at 48 h after thermal stress in mice which appears to be mediated via a MAPK-signaling pathway.
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PMID:Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart. 1145 53

The role of nitric oxide (NO) generated by the inducible NO synthase (iNOS) during myocardial ischemia and reperfusion is not understood. We investigated the role of iNOS during early reperfusion damage induced in genetically deficient iNOS (iNOS-/-) mice and wild-type littermates. In wild-type mice, ischemia (60 min) and reperfusion (60 min) induced an elevation in serum levels of creatine phosphokinase and myocardial injury characterized by the presence of scattered apoptotic myocytes and mild neutrophil infiltration. Northern blot analysis showed increased expression of iNOS, whose activity was markedly elevated after reperfusion. Immunohistochemistry showed staining for nitrotyrosine; Western blot analysis showed elevated expression of heat shock protein 70 (HSP70), a putative cardioprotective mediator. Plasma levels of nitrite and nitrate, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-10 were also increased. These events were preceded by degradation of inhibitor kappaBalpha (IkappaBalpha), activation of IkappaB kinase complex (IKK) and c-Jun-NH2-terminal kinase (JNK), and subsequently activation of nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) as early as 15 min after reperfusion. In contrast, iNOS-/- mice experienced 35% mortality after reperfusion. The extensive myocardial injury was associated with marked apoptosis and infiltration of neutrophils whereas expression of HSP70 was less pronounced. Nitrotyrosine formation and plasma levels of nitrite and nitrate were undetectable. TNF-alpha and IL-6 were increased and IL-10 was reduced in earlier stages of reperfusion. Activation of IKK and JNK and binding activity of NF-kappaB and AP-1 were significantly reduced. Thus, we conclude that iNOS plays a beneficial role in modulating the early defensive inflammatory response against reperfusion injury through regulation of signal transduction.
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PMID:Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-kappaB and AP-1 activation and enhances myocardial damage. 1187 82

The cytokine interleukin-1 (IL-1) has been implicated in ischemic brain damage, because the IL-1 receptor antagonist markedly inhibits experimentally induced neuronal loss. However, to date, no studies have demonstrated the involvement of endogenous IL-1alpha and IL- 1beta in neurodegeneration. We report here, for the first time, that mice lacking IL-1alpha/beta (double knockout) exhibit markedly reduced neuronal loss and apoptotic cell death when exposed to transient cardiac arrest. Furthermore, we show that, despite the reduced neuronal loss, phosphorylation of JNK/SAPK (c-Jun NH2- terminal protein kinase/stress activated protein kinase) and p38 enzymes remain elevated in IL-1 knockout mice. In contrast, the inducible nitric oxide (iNOS) immunoreactivity after global ischemia was reduced in IL-1 knockout mice as compared with wild-type mice. The levels of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) in the hippocampus of wild-type mice were increased with time after ischemia-reperfusion, whereas the increase was significantly inhibited in IL-1 knockout mice. These observations strongly suggest that endogenous IL-1 contributes to ischemic brain damage, and this influence may act through the release of nitric oxide by iNOS.
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PMID:Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1. 1201 30

Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH2) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH2) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.
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PMID:Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. 1219 68

We tested the response of stress-activated mitogen-activated protein kinases (MAPKs) - p38 MAPK and c-JUN NH2-terminal kinase (JNK) - following hypoxia-ischemia (H-I) induced by unilateral carotid artery ligation and hypoxia (8% O2 and 92% N2) for 2.5 h in postnatal-day-7 rats. Phosphorylation of p38 MAPK increased in the hippocampus and cortex immediately following H-I and returned to a basal level 6 h later. In contrast to p38 MAPK, phosphorylation of JNK decreased in the hippocampus and cortex immediately following H-I. Intracerebroventricular administration of two different p38 MAPK inhibitors prior to H-I significantly protected the neonatal brain from H-I injury. Interestingly, p38 MAPK inhibitors did not attenuate caspase-3 activation 24 h after H-I. Thus, these data suggest that p38 MAPKs contribute to the rapid, early component of brain injury following neonatal H-I.
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PMID:Evidence that p38 mitogen-activated protein kinase contributes to neonatal hypoxic-ischemic brain injury. 1264 Jan 79

Antiarrhythmic peptides (AAPs) are a group of compounds with antiarrhythmic properties; however, their use has been hampered by very low plasma stability. The aim of this study was to compare the in vitro and in vivo stability of our new stable AAP analog Ac-d-Tyr-d-Pro-d-Hyp-Gly-d-Ala-Gly-NH2 (ZP123) with the previously described AAP analog AAP10. Moreover, the effect of the two compounds was examined in a murine in vivo model of ouabain-induced second degree AV-block, and the effect on dispersion of action potential duration (APD dispersion) was studied during hypokalemic-ischemia in isolated perfused rabbit hearts. The in vitro t1/2 of ZP123 in rat and human plasma was about 1,700 times longer than t1/2 of AAP10. Due to rapid elimination, it was not possible to obtain an in vivo pharmacokinetic characterization of AAP10; however, calculations suggested that the clearance of ZP123 was at least 140 times slower than for AAP10. AAP10 and ZP123 produced a dose-dependent delay in onset of ouabain-induced AV-block in mice at doses of 10-11 to 10-7 mol/kg i.v. ZP123 and 10-11 to 10-6 mol/kg i.v. AAP10. Maximal efficacy of ZP123 was reached at a 10-fold lower dose (10-8 mol/kg i.v.) than with AAP10. In the isolated rabbit hearts, ZP123 and AAP10 had no effect on dispersion during control conditions. The increased APD dispersion during hypokalemic ischemia is considered a major arrhythmic substrate and only ZP123 prevented the increase in APD dispersion. In conclusion, ZP123 is a new potent AAP analog with improved stability.
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PMID:Pharmacological characterization of the new stable antiarrhythmic peptide analog Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2 (ZP123): in vivo and in vitro studies. 1282 24

Eukaryotic cells respond to different external stimuli by activation of mechanisms of cell signaling. One of the major systems participating in the transduction of signal from the cell membrane to nuclear and other intracellular targets is the highly conserved mitogen-activated protein kinase (MAPK) superfamily. The members of MAPK family are involved in the regulation of a large variety of cellular processes such as cell growth, differentiation, development, cell cycle, death and survival. Several MAPK subfamilies, each with apparently unique signaling pathway, have been identified in the mammalian myocardium. These cascades differ in their upstream activation sequence and in downstream substrate specifity. Each pathway follows the same conserved three-kinase module consisting of MAPK, MAPK kinase (MAPKK, MKK or MEK), and MAPK kinase kinase (MAPKKK, MEKK). The major groups of MAPKs found in cardiac tissue include the extracellular signal-regulated kinases (ERKs), the stress-activated/c-Jun NH2-terminal kinases (SAPK/JNKs), p38-MAPK, and ERK5/big MAPK 1 (BMK1). The ERKs are strongly activated by mitogenic and growth factors and by physical stress, whereas SAPK/JNKs and p38-MAPK can be activated by various cell stresses, such as hyperosmotic shock, metabolic stress or protein synthesis inhibitors, UV radiation, heat shock, cytokines, and ischemia. Activation of MAPKs family plays a key role in the pathogenesis of various processes in the heart, e.g. myocardial hypertrophy and its transition to heart failure, in ischemic and reperfusion injury, as well in the cardioprotection conferred by ischemia- or pharmacologically-induced preconditioning. The following approaches are currently utilized to elucidate the role of MAPKs in the myocardium: (i) studies of the effects of myocardial processes on the activity of these kinases; (ii) pharmacological modulations of MAPKs activity and evaluation of their impact on the (patho)physiological processes in the heart; (iii) gene targeting or expression of constitutively active and dominant-negative forms of enzymes (adenovirus-mediated gene transfer). This review is focused on the regulatory role of MAPKs in the myocardium, with particular regard to their involvement in pathophysiological processes, such as myocardial hypertrophy and heart failure, ischemia/reperfusion injury, as well as in the mechanisms of cardioprotection. In addition, it summarizes current information on pharmacological modulations of MAPKs activity and their impact on the cardiac response to pathophysiological processes.
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PMID:Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. 1284 40

Transient global cerebral ischemia leads to delayed neuronal cell death in the hippocampal CA1, caudate putamen and neocortex. If preischemic hyperglycemia exists, the same duration of ischemia recruits additional brain structures, such as dentate gyrus to become damaged. The objective of the present study is to determine whether activation of mitogen-activated protein kinases (MAPKs) plays a role in hyperglycemia-mediated ischemic neuronal damage. Using phopho-specific antibodies against c-jun NH2-terminal kinase (JNK) and p38 MAPK, we studied activation of these two MAPKs in ischemia-vulnerable neocortex and ischemia-resistant dentate gyrus in rats subjected to 15 min of forebrain ischemia and followed by 0.5, 1 and 3 hr of recirculation under normo- and hyperglycemic conditions. The results showed that levels of phosphorylated JNK increased in both normo- and hyperglycemic brains following blood reperfusion for 0.5 hr and persisted up to 3 hr in the neocortex but not in the dentate gyrus, implying JNK may play a role in mediating neuronal cell death after ischemia. However, since hyperglycemia did not further increase phospho-JNK, JNK may not contribute to the detrimental effect of hyperglycemia on neuronal cell death. The amount of phospho-p38 was not altered by ischemia under both normo- and hyperglycemic conditions, suggesting that p38 MAPK may not play a major role in mediating neuronal damage in these two structures.
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PMID:Effects of hyperglycemic and normoglycemic cerebral ischemia on phosphorylation of c-jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). 1498 93

Recent evidence suggests that activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Thus, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. In the current study, we report that a small molecule, AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile), which has been shown to inhibit the JNK signaling pathway, promotes cell survival after cerebral ischemia. In vivo, AS601245 (40, 60, and 80 mg/kg) administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) was also observed in rats after focal cerebral ischemia. These data suggest that the use of JNK inhibitors such as AS601245 may be a relevant strategy in the therapy of ischemic insults.
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PMID:AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. 1498 19


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