title: Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization.
abstract: 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 [(3)H/(14)C]glucose, and 100 mU/l insulin). Hearts were stressed by transient antecedent IR (2 x 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 microM), adenosine (500 microM), or their combination before severe IR. After severe IR, the phosphorylation (arbitrary density units) of p38 MAPK and AMPK, rates of glucose metabolism (micromol x g dry wt(-1) x 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton Alberta T6G 2H7, Canada.
authors.forename: Jagdip S
authors.initials: JS
authors.lastname: Jaswal
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Barry A
authors.initials: BA
authors.lastname: Finegan
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
mesh_terms: D055372:AMP-Activated Protein Kinases; D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000241:Adenosine; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole