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)

There have been many studies concerning the hemodynamics and physiological mechanisms in ischemic heart disease, little is known about molecular mechanisms during myocardial ischemia in in vivo study. As the signal transduction pathway responsible for myocardial hypertrophy and apoptosis, janus kinase (JAK) and signal transducers and activators of transcription (STAT) are suggested to play an important role. However, whether in vivo activation of JAK-STAT pathway occurs during myocardial ischemia is still unknown. The purpose of this study was to determine whether myocardial JAK or STAT is activated in ischemic heart, and to evaluate the angiotensin blockade on the pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. After myocardial ischemia, we analysed both activated levels and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analyses at 0, 5, 15, 30, 60, 120 and 240 min. Compared with JAK activities at 0 min, JAK1 activities were significantly increased at 60 and 120 min (3.0- and 3.7-fold, respectively, P<0.01). JAK2 and STAT1 activities of ischemic myocardium were unchanged through the time course. STAT3 activities were increased at 5 min (3.3-fold, P<0.01) and markedly enhanced at 30, 60 and 120 min (4.6-, 7.7- and 8.7-fold, respectively, P<0.01). Pretreatment with imidapril (ACE inhibitor) and candesartan cilexitil (AT1 receptor antagonist) significantly prevented the increase in the phosphorylation of JAK1 at 120 min and STAT3 at 30 and 120 min. Sis-inducing factor (SIF) DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in ischemic myocardium. Imidapril and candesartan cilexitil inhibited the activation of SIF DNA binding at 1 day after coronary ligation. In conclusion, we showed that JAK1 and STAT3 were activated by ischemia from the basal activities in in vivo rat myocardial ischemia model. Imidapril and candesartan cilexitil prevented the increase in phosphorylated JAK1 and STAT3, thereby suggesting that angiotensin II, especially angiotensin II type I receptor, partially mediates activation of myocardial JAK-STAT pathway in acute myocardial ischemia.
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PMID:Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats. 1116 35

We recently demonstrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 microm) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.
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PMID:Role of STAT3 in ischemic preconditioning. 1170 38

Recent studies suggest that ischemia activates Src and members of the mitogen-activated protein (MAP) kinase superfamily and their downstream effectors, including big MAP kinase 1 (BMK1) and p90 ribosomal S6 kinase (p90RSK). It has also been reported that adenosine is released during ischemia and involved in triggering the protective mechanism of ischemic preconditioning. To assess the roles of Src and adenosine in ischemia-induced MAP kinases activation, we utilized the Src inhibitor PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (SPT) in perfused guinea pig hearts. PP2 (1 microm) inhibited ischemia-induced Src, BMK1 and JNK activation but not JAK2 and p38 activation. SPT inhibited ischemia-mediated p38 and JNK activation. These results demonstrate that Src family kinase and adenosine regulate MAP kinases by parallel pathways. Preconditioning significantly improved both recovery of developed pressure and dp/dt in isolated guinea pig hearts. Since the protective effect of preconditioning was blocked by PP2 (1 microm) and SPT (50 microm), we next investigated the regulation of Src, MAP kinases and p90RSK during preconditioning. The activity and time course of ERK1/2 was not changed, but p90RSK activation by reperfusion was completely inhibited by preconditioning. In contrast, the activation by ischemia of Src, BMK1, p38 and JNK was significantly faster in preconditioned hearts. Maximal BMK1 activation by ischemia was also significantly enhanced by preconditioning. These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning.
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PMID:Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning. 1170 43

The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury.
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PMID:Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. 1258 43

Understanding transcriptional changes in brain after ischemia may provide therapeutic targets for treating stroke and promoting recovery. To study these changes on a genomic scale, oligonucleotide arrays were used to assess RNA samples from periinfarction cortex of adult Sprague-Dawley rats 24 h after permanent middle cerebral artery occlusions. Of the 328 regulated transcripts in ischemia compared with sham-operated animals, 264 were upregulated, 64 were downregulated, and 163 (49.7%) had not been reported in stroke. Of the functional groups modulated by ischemia: G-protein-related genes were the least reported; and cytokines, chemokines, stress proteins, and cell adhesion and immune molecules were the most highly expressed. Quantitative reverse transcription polymerase chain reaction of 20 selected genes at 2, 4, and 24 h after ischemia showed early upregulated genes (2 h) including Narp, Rad, G33A, HYCP2, Pim-3, Cpg21, JAK2, CELF, Tenascin, and DAF. Late upregulated genes (24 h) included Cathepsin C, Cip-26, Cystatin B, PHAS-I, TBFII, Spr, PRG1, and LPS-binding protein. Glycerol 3-phosphate dehydrogenase, which is involved in mitochondrial reoxidation of glycolysis derived NADH, was regulated more than 60-fold. Plasticity-related transcripts were regulated, including Narp, agrin, and Cpg21. A newly reported lung pathway was also regulated in ischemic brain: C/EBP induction of Egr-1 (NGFI-A) with downstream induction of PAI-1, VEGF, ICAM, IL1, and MIP1. Genes regulated acutely after stroke may modulate cell survival and death; also, late regulated genes may be related to tissue repair and functional recovery.
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PMID:Genomics of the periinfarction cortex after focal cerebral ischemia. 1284 83

We recently demonstrated that ischemic preconditioning (PC) induced by cyclic episodes of short duration of ischemia and reperfusion potentiates a signal transduction cascade involving Janus kinase (JAK) 2 and signal transducer and activator of transcription 3 (STAT3). A rapid activation of JAK and several STATs, including STAT3, STAT5A, and STAT6 also occurred during myocardial ischemia and reperfusion. This study sought to examine whether STAT5A and STAT6 were also involved in PC. Two different animal models were used: isolated perfused working rat hearts and STAT5A and STAT6 knockout mouse hearts. The results of our study indicated phosphorylation of STAT 5A and STAT6 in the preconditioned myocardium. Tyrphostin AG490, a JAK2 inhibitor, or 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-3,4-d-pyrimidine (PPI), a Src kinase blocker, blocked STAT5A phosphorylation, whereas STAT6 phosphorylation was blocked only with tyrphostin. As expected, significant cardioprotection was achieved in the preconditioned heart as evidenced by reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes. PC-mediated cardioprotection was partially abolished when hearts were pretreated with tyrphostin, PPI, or LY-294002, a phosphatidylinositol (PI)-3 kinase inhibitor. Studies with STAT5A and STAT6 knockout mouse hearts revealed that STAT6 knockout mouse hearts, and not STAT5A knockout mouse hearts, were resistant to myocardial ischemia-reperfusion injury. The hearts from STAT5A knockout mice could not be preconditioned, whereas those from STAT6 knockout mice were easily preconditioned. The results of the present study demonstrate that STAT5A, and not STAT6, plays a role in ischemic PC. For the first time, the results also indicated a role of Src kinase pathway in STAT5A PC and PI-3 kinase-Akt pathways appear to be the downstream regulator for STAT5A-STAT6 signaling pathway.
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PMID:STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning. 1286 May 60

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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PMID:Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. 1528 11

The aldose reductase pathway has been demonstrated to be a key component of myocardial ischemia reperfusion injury. Previously, we demonstrated that increased lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, is an important change that drives the metabolic cascade mediating ischemic injury. This study investigated signaling mechanisms by which the aldose reductase pathway mediates myocardial ischemic injury. Specifically, the influence of the aldose reductase pathway flux on JAK-STAT signaling was examined in perfused hearts. Induction of global ischemia in rats resulted in JAK2 activation followed by STAT5 activation. Pharmacological inhibition of aldose reductase or sorbitol dehydrogenase blocked JAK2 and STAT5 activation and was associated with lower lactate/pyruvate ratio and lower protein kinase C activity. Niacin, known to lower cytosolic NADH/NAD+ ratio independent of the aldose reductase pathway inhibition, also blocked JAK2 and STAT5 activation. Inhibition of protein kinase C also blocked JAK2 and STAT5 activation. Transgenic mice overexpressing human aldose reductase exhibited increased JAK2 and STAT5 activation. Pharmacological inhibition of JAK2 reduced ischemic injury and improved functional recovery similar to that observed in aldose reductase pathway inhibited mice hearts. These data, for the first time, demonstrate JAK-STAT signaling by the aldose reductase pathway in ischemic hearts and is, in part, due to changes in cytosolic redox state.
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PMID:Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury. 1574 88

We examined the role for the JAK/STAT signaling pathway in acute opioid-induced cardioprotection (OIC) and whether opioid-induced glycogen synthase kinase-3beta (GSK-3 beta) inhibition is mediated by the JAK/STAT pathway. Rats underwent 30 min of ischemia and either 5 min or 2 h of reperfusion, followed by tissue isolation for molecular analysis or infarct size assessment, respectively. Rats were treated with vehicle, morphine (300 microg/kg), the delta-opioid agonist fentanyl isothiocynate (FIT, 10 microg/kg), or the GSK inhibitor SB-216763 (SB21, 600 microg/kg) 10 min before ischemia. Five minutes before opioid or SB21 treatment, some rats received the putative JAK2 inhibitor AG-490 (3 mg/kg) or the putative JAK3 inhibitor ZM-449829 (3 mg/kg). H9C2 cardiomyoblast cells were also used to investigate FIT-induced signaling (1 microM) in vitro via molecular analysis. Morphine induced the phosphorylation of JAK2, yet not JAK1, in the area at risk. Morphine, FIT, and SB21 also reduced infarct size compared with vehicle (water) when administered before ischemia [43.0 +/- 2.8, 39.1 +/- 3.1, and 42.1 +/- 2.5 (*P < 0.001, respectively) vs. 58.1 +/- 1.3%, respectively]. AG-490 abrogated OIC, whereas ZM-449829 had no effect on OIC. Cardioprotection was afforded by SB21 even in the presence of AG-490. Morphine phosphorylated STAT3, Akt, and GSK-3beta, and phosphorylation was abrogated by AG-490. FIT stimulation of H9C2 cells also caused a time-dependent phosphorylation of STAT3, Akt, and GSK-3beta, and this effect was abrogated by AG-490. STAT3 phosphorylation was also dependent on phosphatidylinositol 3-kinase (PI3K) activation in both tissue and H9C2 cells. These data suggest that OIC occurs via the JAK2 regulation of PI3K pathway-dependent STAT3, Akt, and GSK-3 beta, with GSK-3 beta contributing a central role in acute OIC.
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PMID:The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3 beta. 1651 48

We have shown that renal epithelial cell survival depends on the sustained activation of the extracellular signal-regulated protein kinase (ERK) and lack of this activation was associated with death during oxidative stress. ERK is activated via the canonical epidermal growth factor receptor (EGFR)-Ras-MEK pathway, which could be attenuated by oxidants. We now show that the failure to activate ERK in a sustained manner during severe oxidative stress is owing to the activation of the signal transducer and activator of transcription-3 (STAT3) rather than the failure to activate the EGFR. Tyrosine phosphorylation of the EGFR and STAT3 was studied in hydrogen peroxide (H(2)O(2))-treated mouse proximal tubule (TKPTS) cells or in mouse kidney after ischemia/reperfusion (I/R) injury by Western blotting. STAT3 activation was inhibited by either pharmacologically (AG490) through its upstream janus kinase (JAK2) or by a dominant-negative STAT3 adenovirus. EGFR was inhibited by AG1478. Survival was determined by fluorescence-activated cell sorter analysis and trypan blue exclusion. We found that the EGFR was phosphorylated on its major autophosphorylation site (Tyr1173) regardless of the H(2)O(2) dose. On the other hand, both I/R and severe oxidative stress - but not moderate stress - increased tyrosine phosphorylation of STAT3 in an EGFR and JAK2-dependent manner. Inhibition of JAK2 or STAT3 lead to increased ERK activation and survival of TKPTS cells during severe oxidative stress. Our data suggest a role of tyrosine-phosphorylated STAT3 in the suppression of ERK activation. These data suggest that the STAT3 pathway might represent a new target for improved survival of proximal tubule cells exposed to severe oxidant injury.
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PMID:STAT3 attenuates EGFR-mediated ERK activation and cell survival during oxidant stress in mouse proximal tubular cells. 1678 92


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