Abstract 10957: Sevoflurane Pre-conditioning Ameliorates Myocardial Ischemia/Reperfusion Injury via Cox-2 Expression Inhibition in a Cav-3-dependent, AMPK-Independent Pathway
The inhaled anesthetic sevoflurane has been demonstrated to activate AMP-activated protein kinase (AMPK), upregulate caveolin-3 (Cav3), and protect against myocardial ischemia/reperfusion (MI/R) injury. However, neither the cause-effect relationship between AMPK activation/Cav3 upregulation and sevoflurane cardioprotection, nor the relative contribution of AMPK and Cav3 to sevoflurane cardioprotection has been previously studied. The current study investigated the effect of AMPK inhibition (cardiac specific AMPKα2 dominant negative overexpression, AMPK-DN) and Cav3 knockout (Cav3-KO) upon sevoflurane preconditioning-mediated cardioprotection (SF-PreCon, 3 cycles of 15 minute-exposures to 2% sevoflurane prior to 30 minutes of MI). Apoptosis (caspase-3 activity) was determined 3 hours after R, and infarct size and cardiac function (LVEDP) were determined 24 hours after R. As expected, SF-PreCon in WT decreased caspase-3 activity by 33.7±6.9%, reduced infarct size by 27.9±2.6%, and decreased LVEDP by 36.5±3.2%. Interestingly, the cardioprotective effects of SF-PreCon are only slightly attenuated in AMPK-DK mice when compared to WT (caspase-3 inhibition: 30.8±7.1%, infarct size reduction: 20.5±2.9%, and LVEDP reduction: 29.1±2.3%, P all >0.01). In contrast, SF-PreCon failed to significantly protect Cav3-KO mice against MI/R injury (no statistically significant difference between control and SF-PreCon mice in caspase-3 activity, infarct size, and LVEDP). Moreover, SF-PreCon significantly decreased MI/R-induced superoxide generation (determined by lucigenin luminescence assay) in WT (-53.6±9.1%) as well as in AMPK-DN mice (-43±4.5%, P>0.01), but not in Cav3-KO mice (P>0.05 vs. control). Surprisingly, SF-PreCon had no significant effect upon NADPH oxidase expression, a well-known superoxide production source in MI/R heart. However, SF-PreCon significantly inhibited COX-2 expression (another superoxide source) in WT (-61.7±5.2%) as well as in AMPK-DN mice (-43.2±3.9%), but not in Cav-3KO mice. Collectively, we demonstrate for the first time that Cav3 is more important than AMPK in mediating SF-PreCon cardioprotection, and SF-PreCon ameliorates MI/R injury, at least in part, via Cav3-dependent COX-2 inhibition.
- © 2012 by American Heart Association, Inc.