Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts
Free accessResearch articleFirst published online December, 2003
Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts
Background: The stress-responsive mitogen-activated protein kinases (MAPKs) (p38-MAPK, c-Jun NH2-terminal kinase [JNK-1 and JNK-2], and extracellular signal regulated kinases [ERK-1 and ERK-2]) might be involved in angiotensin II (AIJ)-induced ischemiareperfusion injury. Cardioprotection induced by All type 1 (AT1) and type 2 (AT2) receptor blockade during ischemia-reperfusion is associated with protein kinase Cc (PKCe), nitric oxide, and cyclic guanosine monophosphate (cGMP) signaling. Our aim was to assess the effect of selective AT, and AT2 receptor blockade with losartan and PD123,319, respectively, on MAPK expression after ischemia-reperfusion in isolated working rat hearts.
Methods: Groups of six hearts were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes) and exposed to no drug/no ischemia-reperfusion (control), ischemia-reperfusionlno drug, and ischemia-reperfusion with losartan (1 MM), or PD123,319 (0.3,uM) and additional groups. AT,/AT2 receptor expression, MAPKs, PKCE, and cGMP, and changes in mechanical function were measured. Western blotting was done on left ventricular tissue for AT,/AT2, p38/phosphorylated-p38 (p-p38), phosphorylated (p)-JNK-1/-2, phosphorylated (p)-ERK-1/-2, and PKCe proteins; Northern blots for AT,/AT2 mRNA; and enzyme immunoassay for cGMP.
Results: Compared with controls, ischemia-reperfusion induced significant left ventricular dysfunction, decreased AT2 protein and mRNA, increased p-p38 and p-JNK-1/-2, did not change p-ERK-1/-2 or PKCe, and decreased cGMP. PD123,319 improved left ventricular recovery after ischemia-reperfusion, increased AT2 protein and mRNA, mildly increased p-p38, normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCe and cGMP. Losartan did not change p-p38, increased p-JNK-1, and did not change pERK- 1/-2, PKCe, or cGMP.
Conclusions: The overall results suggest that the activation of p38-MAPK and JNK might be linked to All signaling and play a significant role in acute ischemia-reperfusion injury as well as in the cardioprotective effect of AT2 receptor blockade.
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