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Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts

Cardiovascular Research Center, Department of Medicine, University of Wisconsin, Madison, Wisconsin

Vijayan Menon, MSc

Cardiology Division of the Department of Medicine, and the Cardiovascular Research Group, University of Alberta, Edmonton, Alberta

William R. Ford, PhD

Welsh School of Pharmacy, Cardiff University, Cardiff UK

Alexander S. Clanachan, PhD

Cardiology Division of the Department of Medicine, and the Cardiovascular Research Group, University of Alberta, Edmonton, Alberta

Bodh I. Jugdutt, MD, MSc, FRCPC

Cardiology Division of the Department of Medicine, and the Cardiovascular Research Group, University of Alberta, Edmonton, Alberta; 2C2.43 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R7; bjugdutt{at}ualberta.ca

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.

Key Words: angiotensin • ischemia • protein kinases • receptors • reperfusion

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 8, No. 4, 285-296 (2003)
DOI: 10.1177/107424840300800406


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