Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization

2007 ◽  
Vol 293 (2) ◽  
pp. H1107-H1114 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
P38 Mapk ◽  
Glucose Utilization ◽  
Ischemia Reperfusion ◽  
Glycogen Synthesis ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor

p38 mitogen-activated protein kinase (MAPK) and 5′-AMP-activated protein kinase (AMPK) are activated by metabolic stresses and are implicated in the regulation of glucose utilization and ischemia-reperfusion (IR) injury. This study tested the hypothesis that inhibition of p38 MAPK restores the cardioprotective effects of adenosine in stressed hearts by preventing activation of AMPK and the uncoupling of glycolysis from glucose oxidation. Working rat hearts were perfused with Krebs solution (1.2 mM palmitate, 11 mM [3H/14C]glucose, and 100 mU/l insulin). Hearts were stressed by transient antecedent IR (2 × 10 min I/5 min R) before severe IR (30 min I/30 min R). Hearts were treated with vehicle, p38 MAPK inhibitor (SB-202190, 10 μM), adenosine (500 μM), or their combination before severe IR. After severe IR, the phosphorylation (arbitrary density units) of p38 MAPK and AMPK, rates of glucose metabolism (μmol·g dry wt−1·min−1), and recovery of left ventricular (LV) work (Joules) were similar in vehicle-, SB-202190- and adenosine-treated hearts. Treatment with SB-202190 + adenosine versus adenosine alone decreased p38 MAPK (0.03 ± 0.01, n = 3 vs. 0.48 ± 0.10, n = 3, P < 0.05) and AMPK (0.00 ± 0.00, n = 3 vs. 0.26 ± 0.08, n = 3 P < 0.05) phosphorylation. This was accompanied by attenuated rates of glycolysis (1.51 ± 0.40, n = 7 vs. 3.95 ± 0.65, n = 7, P < 0.05) and H+ production (2.12 ± 0.76, n = 7 vs. 6.96 ± 1.48, n = 7, P < 0.05), and increased glycogen synthesis (1.91 ± 0.25, n = 6 vs. 0.27 ± 0.28, n = 6, P < 0.05) and improved recovery of LV work (0.81 ± 0.08, n = 7 vs. 0.30 ± 0.15, n = 8, P < 0.05). These data indicate that inhibition of p38 MAPK abolishes subsequent phosphorylation of AMPK and improves the coupling of glucose metabolism, thereby restoring adenosine-induced cardioprotection.

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

2007 ◽  
Vol 292 (4) ◽  
pp. H1978-H1985 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Mitogen Activated Protein Kinase ◽  
Transient Ischemia ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Ampk Activity ◽  
Mapk Inhibitors

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts

2021 ◽  
Vol 99 (2) ◽  
pp. 218-223
Author(s):  
Mohamad Nusier ◽  
Mohammad Alqudah ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Infarct Size ◽  
P38 Mapk ◽  
Ischemic Preconditioning ◽  
Creatine Phosphokinase ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Normal Heart ◽  
Mitogen Activated Protein

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.

scholarly journals Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart

1998 ◽  
Vol 332 (2) ◽  
pp. 459-465 ◽  
Author(s):  
Antigone LAZOU ◽  
Peter H. SUGDEN ◽  
Angela CLERK
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Hypertrophic Growth ◽  
Mitogen Activated Protein ◽  
Powerful Activator ◽  
P38 Mapk Inhibitor ◽  
Cellular Stresses ◽  
P38 Mapks

We investigated the ability of phenylephrine (PE), an α-adrenergic agonist and promoter of hypertrophic growth in the ventricular myocyte, to activate the three best-characterized mitogen-activated protein kinase (MAPK) subfamilies, namely p38-MAPKs, SAPKs/JNKs (i.e. stress-activated protein kinases/c-Jun N-terminal kinases) and ERKs (extracellularly responsive kinases), in perfused contracting rat hearts. Perfusion of hearts with 100 µM PE caused a rapid (maximal at 10 min) 12-fold activation of two p38-MAPK isoforms, as measured by subsequent phosphorylation of a p38-MAPK substrate, recombinant MAPK-activated protein kinase 2 (MAPKAPK2). This activation coincided with phosphorylation of p38-MAPK. Endogenous MAPKAPK2 was activated 4–5-fold in these perfusions and this was inhibited completely by the p38-MAPK inhibitor, SB203580 (10 µM). Activation of p38-MAPK and MAPKAPK2 was also detected in non-contracting hearts perfused with PE, indicating that the effects were not dependent on the positive inotropic/chronotropic properties of the agonist. Although SAPKs/JNKs were also rapidly activated, the activation (2–3-fold) was less than that of p38-MAPK. The ERKs were activated by perfusion with PE and the activation was at least 50% of that seen with 1 µM PMA, the most powerful activator of the ERKs yet identified in cardiac myocytes. These results indicate that, in addition to the ERKs, two MAPK subfamilies, whose activation is more usually associated with cellular stresses, are activated by the Gq/11-protein-coupled receptor (Gq/11PCR) agonist, PE, in whole hearts. These data indicate that Gq/11PCR agonists activate multiple MAPK signalling pathways in the heart, all of which may contribute to the overall response (e.g. the development of the hypertrophic phenotype).

scholarly journals The Proto-oncoprotein Brx Activates Estrogen Receptor β by a p38 Mitogen-activated Protein Kinase Pathway

2001 ◽  
Vol 276 (50) ◽  
pp. 46792-46797 ◽  
Author(s):  
Paul H. Driggers ◽  
James H. Segars ◽  
Domenica M. Rubino
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Active Form ◽  
Mitogen Activated Protein Kinase ◽  
The Novel ◽  
Mapk Activity ◽  
Dependent Activity ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERα via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERβ. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERβ activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERβ function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the β2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERβ. Our findings suggest that p38 MAPKs may be important regulators of ERβ activity.

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

2008 ◽  
Vol 294 (1) ◽  
pp. E183-E189 ◽  
Author(s):  
Weidong Chai ◽  
Yangsong Wu ◽  
Guolian Li ◽  
Wenhong Cao ◽  
Zequan Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
P38 Mapk ◽  
Myocardial Protection ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia-reperfusion injury contributes significantly to morbidity and mortality in patients with diabetes. Insulin decreases myocardial infarct size in animals and the rate of apoptosis in cultured cells. Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. A euglycemic clamp (3 mU·min−1·kg−1) was begun either 10 min before ischemia (InsulinBI), 5 min before reperfusion (InsulinBR), or 30 min after the onset of reperfusion (InsulinAR), and continued until the end of the study. Compared with saline control, insulin decreased the infarct size in both InsulinBI ( P < 0.001) and InsulinBR ( P < 0.02) rats but not in InsulinAR rats. The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. However, it completely abolished insulin's protective effect in InsulinBI and InsulinBR rats. Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in InsulinAR rats. We conclude that insulin protects myocardium against ischemia-reperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect.

scholarly journals Protective action of the ginsenoside Rh3 in a rat myocardial ischemia-reperfusion injury model by inhibition of apoptosis induced via p38 mitogen-activated protein kinase/caspase-3 signaling

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052096909
Author(s):  
Liexiang Cao ◽  
Yi Gao ◽  
Jinqiang Zhu ◽  
Jinbo Zhang ◽  
Meiping Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Protein Kinase ◽  
Myocardial Ischemia ◽  
P38 Mapk ◽  
Caspase 3 ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Myocardial Ischemia Reperfusion

Objective To investigate the protective effects of the ginsenoside Rh3 on rats subjected to myocardial ischemia-reperfusion (MIR) via its impact on caspase-3 and the p38 mitogen-activated protein kinase (MAPK) pathway. Methods Fifteen male Sprague-Dawley rats were randomly categorized into the MIR group (MY group, n = 5), sham surgery group (SS group, n = 5), and ginsenoside Rh3 group (GR group, n = 5). Results The MY group exhibited the largest myocardial infarctions compared with the GR and SS groups. The GR group exhibited significantly higher cell viability of cardiomyocytes and significantly decreased apoptosis compared with the MY group. Fibrils of infarcted tissue in the GR group were disordered but less swollen, with a more organized fibril orientation than those in the MY group. The GR group showed reduced p-p38 MAPK protein and caspase-3 mRNA expression levels compared with the MY and SS groups. Conclusions Rh3 significantly improved myocardial necrosis and caspase-3 levels in myocardial tissues by suppressing the p38 MAPK pathway, thereby inhibiting caspase-3 involvement in apoptosis. Thus, Rh3 was effective in inhibiting the escalated apoptotic pathway in myocardial infarction and can potentially serve as a useful therapeutic agent to rescue myocardial infarction.

scholarly journals Role of the p38 Mitogen-Activated Protein Kinase/Cytosolic Phospholipase A2 Signaling Pathway in Blood—Brain Barrier Disruption after Focal Cerebral Ischemia and Reperfusion

2008 ◽  
Vol 28 (10) ◽  
pp. 1686-1696 ◽  
Author(s):  
Chikako Nito ◽  
Hiroshi Kamada ◽  
Hidenori Endo ◽  
Kuniyasu Niizuma ◽  
D Jeannie Myer ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cerebral Ischemia ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Ischemia Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Cytosolic Phospholipase ◽  
Mitogen Activated Protein

Cytosolic phospholipase A2 (cPLA2) is a key enzyme that mediates arachidonic acid metabolism, which causes cerebral ischemia-induced oxidative injury, blood—brain barrier (BBB) dysfunction, and edema. Recent reports have shown that p38 mitogen—activated protein kinase (MAPK) is related to phosphorylation and activation of cPLA2 and release of arachidonic acid. However, involvement of the p38 MAPK pathway in cPLA2 activation and of reactive oxygen species in expression of p38 MAPK/cPLA2 after ischemia—reperfusion injury in the brain remains unclear. To address these issues, we used a model of transient focal cerebral ischemia (tFCI) in rats. Western blot analysis showed a significant increase in expression of phospho-p38 MAPK and phospho-cPLA2 in rat brain cortex after tFCI. Activity assays showed that both p38 MAPK and cPLA2 activation markedly increased 1 day after reperfusion. Intraventricular administration of SB203580 significantly suppressed activation and phosphorylation of cPLA2 and attenuated BBB extravasation and subsequent edema. Moreover, overexpression of copper/zinc-superoxide dismutase remarkably diminished activation and phosphorylation of both p38 MAPK and cPLA2 after reperfusion. These findings suggest that the p38 MAPK/cPLA2 pathway may promote BBB disruption with secondary vasogenic edema and that superoxide anions can stimulate this pathway after ischemia—reperfusion injury.

scholarly journals Cross-talk between IRAK-4 and the NADPH oxidase1

2007 ◽  
Vol 403 (3) ◽  
pp. 451-461 ◽  
Author(s):  
Sandrine Pacquelet ◽  
Jennifer L. Johnson ◽  
Beverly A. Ellis ◽  
Agnieszka A. Brzezinska ◽  
William S. Lane ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Free System ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Tlr4 Activation

Exposure of neutrophils to LPS (lipopolysaccharide) triggers their oxidative response. However, the relationship between the signalling downstream of TLR4 (Toll-like receptor 4) after LPS stimulation and the activation of the oxidase remains elusive. Phosphorylation of the cytosolic factor p47phox is essential for activation of the NADPH oxidase. In the present study, we examined the hypothesis that IRAK-4 (interleukin-1 receptor-associated kinase-4), the main regulatory kinase downstream of TLR4 activation, regulates the NADPH oxidase through phosphorylation of p47phox. We show that p47phox is a substrate for IRAK-4. Unlike PKC (protein kinase C), IRAK-4 phosphorylates p47phox not only at serine residues, but also at threonine residues. Target residues were identified by tandem MS, revealing a novel threonine-rich regulatory domain. We also show that p47phox is phosphorylated in granulocytes in response to LPS stimulation. LPS-dependent phosphorylation of p47phox was enhanced by the inhibition of p38 MAPK (mitogen-activated protein kinase), confirming that the kinase operates upstream of p38 MAPK. IRAK-4-phosphorylated p47phox activated the NADPH oxidase in a cell-free system, and IRAK-4 overexpression increased NADPH oxidase activity in response to LPS. We have shown that endogenous IRAK-4 interacts with p47phox and they co-localize at the plasma membrane after LPS stimulation, using immunoprecipitation assays and immunofluorescence microscopy respectively. IRAK-4 was activated in neutrophils in response to LPS stimulation. We found that Thr133, Ser288 and Thr356, targets for IRAK-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after LPS stimulation. We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

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