Abstract 11302: Sevoflurane Pre-Conditioning Effectively Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury via Differential Regulation of p38 and ERK

Abstract

Diabetes (DB) significantly exacerbates myocardial ischemia/reperfusion (MI/R) injury. Unfortunately, conventional pre-conditioning (PreCon) provides diminished cardioprotection during DB, due partially to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon by inhaled anesthetic sevoflurane (SF-PreCon) remains protective in DB, and if so, to dissect the involved mechanisms. Non-diabetic (ND) or high-fat diet-induced DB mice were subjected to MI/R and randomized into control and SF-PreCon (3 cycles of 15 minute-exposures to 2% sevoflurane prior to MI) groups. As expected, SF-PreCon significantly reduced MI/R injury in ND mice. Importantly, SF-PreCon also significantly reduced MI/R injury in DB mice, as evidenced by reduced apoptosis (-23.1±1.6, P<0.01), decreased infarct size (-21.2±2.3%, P<0.01), and augmented cardiac function (+24±3.0%, P<0.01). To determine the role of AMPK in SF-PreCon-mediated cardioprotection, the effect of SF-PreCon upon MI/R injury was determined in cardiac specific AMPKα2 dominant negative overexpression mice (AMPK-DN). We demonstrate SF-PreCon remained cardioprotective in AMPK-DN mice. To explore the responsible molecular mechanisms, multiple cell-survival signaling molecules were screened. Interestingly, SF-PreCon differentially regulated mitogen-activated protein kinase (MAPK) family members in the MI/R heart. In ND mice, SF-PreCon dramatically reduced (-81±7.2%) MI/R-induced activation of p38, a pro-death MAPK, without significantly altering ERK and JNK. In DB and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted (DB: -8±2.1%) or virtually abolished (AMPK-DN). However, SF-PreCon significantly increased (P<0.05) phosphorylation of ERK1/2, a pro-survival MAPK. Collectively, we demonstrate SF-PreCon protected the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts its cardioprotective actions via AMPK-independent activation of pro-survival MAPK in DB mice. These results suggest SF-PreCon may be a superior intervention over conventional PreCon in DB patients, where AMPK signaling is impaired.