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(Hypertension. 2000;36:506.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade

Yi Xu; Alexander S. Clanachan; Bodh I. Jugdutt

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

Abstract—We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT₂R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT₂R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP₃R) and protein kinase C (PKC) proteins. We assessed AT₂R, angiotensin II type 1 receptor (AT₁R), IP₃R, and PKC protein expression (Western blots) and AT₂R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (n=6) were exposed to no IR, no IR+PD (0.3 µmol/L), IR, and IR+PD. Compared with no IR and no IR+PD, IR decreased (P<0.05) functional recovery and AT₂R mRNA and protein, as well as AT₁R mRNA (not protein) and IP₃R and PKC proteins. Compared with IR, PD+IR improved LV functional recovery (P<0.05) and markedly increased AT₂R mRNA and protein (P<0.001). However, PD did not change AT₁R mRNA or protein. More importantly, PD+IR markedly increased IP₃R and PKC proteins. The downregulation of AT₂R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT₂R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT₂R blockade and is associated with enhanced downstream IP₃R and PKC signaling.

Key Words: angiotensin II • mRNA • inositol • protein kinases • ischemia

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