Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion.
Mitogen-activated protein kinases (MAPKs) have been implicated during ischemia-reperfusion (IR) and angiotensin II (AngII) type 2 receptor (AT2R) blockade has been shown to induce cardioprotection involving protein kinase Cepsilon (PKCepsilon) signaling after IR. We examined whether the 3 major MAPKs, p38, c-Jun NH2-terminal kinase (JNK-1 and JNK-2), and extracellular signal regulated kinases (ERK-1 and ERK-2) are activated after IR and whether treatment with the AT2R antagonist PD123,319 (PD) alters their expression. Isolated rat hearts were randomized to control (aerobic perfusion, 80 min), IR (no drug; 50 min of perfusion, 30 min global ischemia and 30 min reperfusion; working mode), and IR + PD (0.3 micromol/l) and left ventricular (LV) work was measured. We measured LV tissue content of p38, p-p38, p-JNK-1 (54 kDa), p-JNK-2 (46 kDa), p-ERK-1 (44 kDa), p-ERK-2 (42 kDa) and PKCepsilon proteins by immunoblotting and cGMP by enzyme immunoassay. IR resulted in significant LV dysfunction, increase in p-p38 and p-JNK-1/-2, no change in p-ERK-1/-2 or PKCepsilon, and decrease in cGMP. PD improved LV recovery after IR, induced a slight increase in p-p38 (p < 0.01 vs. control), normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCepsilon and cGMP. The overall results suggest that p38 and JNK might play a significant role in acute IR injury and the cardioprotective effect of AT2R blockade independent of ERK. The activation of p38 and JNKs during IR may be linked, in part, to AT2R stimulation.
Kumar
Dinender
D
Cardiology Division of the Department of Medicine and the Cardiovascular Research Group, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Menon
Vijayan
V
Ford
William R
WR
Clanachan
Alexander S
AS
Jugdutt
Bodh I
BI
D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; C073402:PD 123319; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP