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Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion

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Abstract

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 Cε-(PKCε) 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 μmol/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 PKCε 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 PKCε, 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 PKCε 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.

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Authors and Affiliations

  1. Cardiology Division of the Department of Medicine and the Cardiovascular Research Group, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Dinender Kumar, Vijayan Menon, William R. Ford, Alexander S. Clanachan & Bodh I. Jugdutt

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  1. Dinender Kumar
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  4. Alexander S. Clanachan
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Kumar, D., Menon, V., Ford, W.R. et al. Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion. Mol Cell Biochem 258, 211–218 (2004). https://doi.org/10.1023/B:MCBI.0000012857.06723.81

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