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 Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes

2000 ◽  
Vol 350 (3) ◽  
pp. 891-899 ◽  
Author(s):  
Anu PUNN ◽  
James W. MOCKRIDGE ◽  
Saleha FAROOQUI ◽  
Michael S. MARBER ◽  
Richard J. HEADS
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Cell Injury ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Sustained Activation

Delayed cytoprotection (preconditioning) occurs 24h after sublethal simulated ischaemia and reperfusion (SI/R) in neonatal rat ventricular cardiomyocytes. SI/R was used to investigate the role of activation of mitogen-activated protein kinases (MAPKs), stress-activated protein kinases (SAPKs) and phosphoinositide 3-kinase-dependent protein kinase B (PKB)/Akt in cytoprotection. SI resulted in transient dual (Thr/Tyr) phosphorylation of p42/p44-MAPK and p38-MAPK, weak phosphorylation of p46/p54-SAPK, but no phosphorylation of PKB. ‘Reperfusion’ caused further transient phosphorylation of p38-MAPK, but sustained phosphorylation of p42/p44-MAPK (lasting 4h) and of Ser473 of PKB (lasting 2h). Furthermore, SI/R (24h) induced delayed protection against lethal SI, as determined by an increase in cell viability {bioreduction of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide]} and a decrease in cell injury (release of creatine kinase). Both protection and phosphorylation of p42/p44-MAPK were blocked by the MEK-1/2 (MAPK/Erk kinase-1/2) inhibitor PD98059 (50µM) when given during SI/R, but not when given during SI alone. The p38-MAPK inhibitor SB203580 (10µM) blocked the p38-MAPK-dependent phosphorylation of activating transcription factor 2 in vitro, and the phosphoinositide 3-kinase inhibitor wortmannin (100nM) blocked PKB phosphorylation on Ser473. However, neither SB203580 nor wortmannin had any effect on delayed protection. Therefore sustained activation of p42/p44-MAPK during simulated ‘reperfusion’ following sublethal SI mediates preconditioning in cardiomyocytes independently of transient activation of p38-MAPK or sustained activation of PKB.

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.

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.

scholarly journals Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases

2006 ◽  
Vol 395 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Michela Capano ◽  
Martin Crompton
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Fluorescent Protein ◽  
Mitogen Activated Protein Kinase ◽  
Heart Cells ◽  
Intermembrane Space ◽  
Neonatal Cardiomyocytes ◽  
Mitogen Activated Protein ◽  
Green Fluorescent

The cytosolic protein Bax plays a key role in apoptosis by migrating to mitochondria and releasing proapoptotic proteins from the mitochondrial intermembrane space. The present study investigates the movement of Bax in isolated rat neonatal cardiomyocytes subjected to simulated ischaemia (minus glucose, plus cyanide), using green fluorescent protein-tagged Bax as a means of imaging Bax movements. Simulated ischaemia induced Bax translocation from the cytosol to mitochondria, commencing within 20 min of simulated ischaemia and progressing for several hours. Under the same conditions, there was an increase in the active, phosphorylated forms of p38 MAPK (mitogen-activated protein kinase) and AMPK (AMP-activated protein kinase). The AMPK activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin also stimulated Bax translocation. Inhibition of p38 MAPK with SB203580 attenuated the phosphorylation of the downstream substrates, MAPK-activated protein kinases 2 and 3, but not that of the upstream MAPK kinase 3, nor of AMPK. Under all conditions (ischaemia, AICAR and metformin), SB203580 blocked Bax translocation completely. It is concluded that Bax translocation to mitochondria is an early step in ischaemia and that it occurs in response to activation of p38 MAPK downstream of AMPK.

scholarly journals Cholesterol is the major component of native lipoproteins activating the p38 mitogen-activated protein kinases

2005 ◽  
Vol 386 (9) ◽  
pp. 909-918 ◽  
Author(s):  
Iveta Dobreva ◽  
Olaf Zschörnig ◽  
Gérard Waeber ◽  
Richard W. James ◽  
Christian Widmann
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Cholesterol Content ◽  
Mitogen Activated Protein Kinase ◽  
High Density Lipoproteins ◽  
Ldl Particles ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein ◽  
P38 Mapks

Abstract Elevated low-density lipoprotein (LDL) levels induce activation of the p38 mitogen-activated protein kinase (MAPK), a stress-activated protein kinase potentially participating in the development of atherosclerosis. The nature of the lipoprotein components inducing p38 MAPK activation has remained unclear however. We show here that both LDLs and high-density lipoproteins (HDLs) have the ability to stimulate the p38 MAPKs with potencies that correlate with their cholesterol content. Cholesterol solubilized in methyl-β-cyclodextrin was sufficient to activate the p38 MAPK pathway. Liposomes made of phosphatidylcholine (PC) or sphingomyelin, the two main phospholipids found in lipoproteins, were unable to stimulate the p38 MAPKs. In contrast, PC liposomes loaded with cholesterol potently activated this pathway. Reducing the cholesterol content of LDL particles lowered their ability to activate the p38 MAPKs. Cell lines representative of the three main cell types found in blood vessels (endothelial cells, smooth muscle cells and fibroblasts) all activated their p38 MAPK pathway in response to LDLs or cholesterol-loaded PC liposomes. These results indicate that elevated cholesterol content in lipoproteins, as seen in hypercholesterolemia, favors the activation of the stress-activated p38 MAPK pathway in cells from the vessel wall, an event that might contribute to the development of atherosclerosis.

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