Abstract 9827: Acute Rosiglitazone Treatment is Cardioprotective Against Ischemia/Reperfusion Injury by Modulating AMPK, Akt, and JNK Signaling 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 concept remains controversial as recent evidence has suggested an increased risk of cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a non-diabetic mouse model.
Methods and Results: Non-diabetic FVB/NJ mice were subjected to left anterior descending coronary artery occlusion for 20 min followed by 4 h of reperfusion and given RGZ (1 µg/g i.v.) 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared to vehicle controls (9% ± 1% vs. 20% ± 4%, P<0.05) and post-ischemic recovery in isolated perfused hearts (no flow ischemia 20 min, reperfusion 30 min) was significantly improved with RGZ administered at reperfusion compared to vehicle (P<0.001). To investigate the signaling mechanisms of RGZ-induced cardioprotection, mice were subjected to 20 min of in vivo regional ischemia and 10 min of reperfusion. The levels of both p-AMPK (Thr172) and p-Akt (Ser473) were significantly increased when RGZ was given 5 min before reperfusion compared to vehicle (P<0.01 and P<0.05, respectively). On the other hand, p-JNK (Thr183/Tyr185) was significantly decreased as a result of RGZ treatment compared to vehicle (P<0.05). Pre-treatment with the selective PPAR-γ inhibitor GW-9662 (1 µg/g i.v.) 10 min before reperfusion significantly decreased both p-AMPK and p-Akt levels and did not decrease p-JNK levels in the heart during I/R. Moreover, mice pre-treated with the AMPK inhibitor compound C (10 μ g/g i.p.) and given RGZ 5 min before reperfusion did not exhibit a significant decrease in infarct size compared to RGZ alone.
Conclusions: Taken together, acute treatment with RGZ can reduce ischemic injury in a non-diabetic mouse heart via modulating AMPK, Akt, and JNK signaling pathways. Although the use of RGZ pertains exclusively to patients with type 2 diabetes, the use of acute RGZ therapy to non-diabetic patients may be a potential beneficial treatment for I/R injury.
- © 2011 by American Heart Association, Inc.