title: Myocardial ischemia/reperfusion causes VDAC phosphorylation which is reduced by cardioprotection with a p38 MAP kinase inhibitor.
abstract: 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.
authors: Department of Internal Medicine III, Martin-Luther-University, Halle-Wittenberg, Halle/Saale, Germany.
authors: Hansjörg
authors: H
authors: Schwertz
authors: Justin M
authors: JM
authors: Carter
authors: Mulati
authors: M
authors: Abdudureheman
authors: Martin
authors: M
authors: Russ
authors: Ute
authors: U
authors: Buerke
authors: Axel
authors: A
authors: Schlitt
authors: Ursula
authors: U
authors: Müller-Werdan
authors: Roland
authors: R
authors: Prondzinsky
authors: Karl
authors: K
authors: Werdan
authors: Michael
authors: M
authors: Buerke
mesh_terms: 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*
chemical_list: 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