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Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2007 Aug; Vol. 293 (2), pp. H1107-14. Date of Electronic Publication: 2007 May 11. - Publication Year :
- 2007
-
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.
- Subjects :
- AMP-Activated Protein Kinases
Adenosine pharmacology
Animals
Cardiotonic Agents pharmacology
Disease Models, Animal
Glycogen metabolism
Glycolysis drug effects
Hydrogen-Ion Concentration
Imidazoles pharmacology
In Vitro Techniques
Male
Multienzyme Complexes metabolism
Myocardial Ischemia drug therapy
Myocardial Ischemia enzymology
Myocardial Ischemia metabolism
Myocardial Ischemia physiopathology
Myocardial Reperfusion Injury enzymology
Myocardial Reperfusion Injury etiology
Myocardial Reperfusion Injury metabolism
Myocardial Reperfusion Injury physiopathology
Myocardium enzymology
Phosphorylation
Protein Kinase Inhibitors therapeutic use
Protein Serine-Threonine Kinases metabolism
Pyridines pharmacology
Rats
Rats, Sprague-Dawley
Severity of Illness Index
Ventricular Function, Left drug effects
p38 Mitogen-Activated Protein Kinases metabolism
Adenosine metabolism
Cardiotonic Agents metabolism
Glucose metabolism
Multienzyme Complexes antagonists & inhibitors
Myocardial Ischemia complications
Myocardial Reperfusion Injury prevention & control
Myocardium metabolism
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 293
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 17496214
- Full Text :
- https://doi.org/10.1152/ajpheart.00455.2007