Abstract 21: Acute Rosiglitazone Treatment Activates Cardioprotective Signaling During Ischemia/Reperfusion in Non-Diabetic Mice
Background: Rosiglitazone (RGZ), a PPAR-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia/reperfusion (I/R), however, this notion remains controversial. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by activating well known cardioprotective signaling pathways.
Methods and Results: Non-diabetic FVB/NJ mice were subjected to left anterior descending coronary artery occlusion for 20 minutes followed by 10 minutes of reperfusion in order to detect the signaling activity in the left ventricle. This study contained six experimental groups in order to address whether the cardioprotective signaling mediated by RGZ was dependent or independent on PPAR-γ activation by using a selective PPAR-γ inhibitor, GW-9662; Sham+Vehicle, Sham+RGZ (1μg/g), I/R+Vehicle, I/R+RGZ, I/R+GW-9662 (1μg/g), and I/R+ GW-9662+RGZ. All treatments were administered by intraperitoneal injection (RGZ given at 5 minutes prior to reperfusion and GW-9662 given at 10 minutes prior). The results revealed that phospho-Akt (Ser473) levels significantly increased when RGZ was administered before reperfusion compared to vehicle (4-fold increase, p<0.05, n=3) and when compared to GW-9662 administration followed by RGZ treatment (4-fold increase, p<0.05, n=3). There was no significant change in Akt activation from RGZ treatment during sham operation. Furthermore, phospho-AMPK (Thr172) levels also increased when RGZ was administered prior to reperfusion compared to vehicle. Interestingly, when GW-9662 was administered followed by RGZ treatment, phospho-AMPK levels drastically increased compared to vehicle and GW-9662 alone (both 4.4-fold increase, p<0.01, n=3). RGZ during sham operation slightly increased phospho-AMPK levels compared to vehicle (p=NS).
Conclusions: Acute treatment with RGZ activates key signaling pathways that are known to mediate cardioprotection during ischemia/reperfusion. Moreover, the data suggests that Akt activation by RGZ is dependent on PPAR-γ and that AMPK activation by RGZ is independent of PPAR-γ. Further investigations are needed to elucidate the cardioprotective potential of RGZ on ischemic injury.
- © 2010 by American Heart Association, Inc.