Myocardial ischemia/reperfusion causes VDAC phosphorylation which is reduced by cardioprotection with a p38 MAP kinase inhibitor.
Myocardial ischemia (MI) and reperfusion (R) results in activation of the p38 MAP kinase pathway. This pathway phosphorylates transcription factors and cytoplasmic proteins leading to expression of adhesion molecules and cytokines, increased neutrophil activation, and finally, myocardial necrosis and apoptosis. We studied the effects of a p38 MAP kinase inhibitor, PD169316, on cardioprotection, protein expression, and tyrosine phosphorylation, in a rabbit model of 1 h of (MI) and 3 h of (R). PD169316 administered just before (R) significantly reduced myocardial neutrophil accumulation, necrosis area (28.4 +/- 7.9% vs. 56.4 +/- 7.9% necrosis/AAR), and CK release compared to a vehicle treated group (p<0.05). We found several proteins altered in expression following MI + R alone or with p38 inhibition including myofilament proteins, energetics proteins, heat shock proteins, and the mitochondrial porin VDAC-1. p38 MAPK inhibition significantly reduced the phosphorylation of VDAC-1 which is a known mitochondrial regulator of cell survival. Thus, p38 MAP kinase inhibition with PD169316 is cardioprotective, reduces neutrophil activation, and controls protein expression and phosphorylation in MI and reperfusion.
Schwertz
Hansjörg
H
Department of Internal Medicine III, Martin-Luther-University, Halle-Wittenberg, Halle/Saale, Germany.
Carter
Justin M
JM
Abdudureheman
Mulati
M
Russ
Martin
M
Buerke
Ute
U
Schlitt
Axel
A
Müller-Werdan
Ursula
U
Prondzinsky
Roland
R
Werdan
Karl
K
Buerke
Michael
M
D000818:Animals; D045163:Antibodies, Phospho-Specific; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D011817:Rabbits; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D045163:Antibodies, Phospho-Specific; D002316:Cardiotonic Agents; D007093:Imidazoles; D020543:Proteome; D050994:Voltage-Dependent Anion Channels; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole