Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

BACKGROUND:Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood. METHODS:In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 & mu;g/kg DEX was performed 20 minutes before ligation. Moreover, the & alpha;2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment. RESULTS:In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 & PLUSMN; 0.165 vs 1.55 & PLUSMN; 0.183; P < .0001), downregulated the inflammatory response (P & LE; .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis (P = .0074), and promoted the phosphorylation of STAT3 (4.94 & PLUSMN; 0.690 vs 6.68 & PLUSMN; 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 & mu;M DEX pretreatment improved cell viability (P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P & LE; .0040), decreased cell apoptosis (P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 & PLUSMN; 0.0224 vs 0.297 & PLUSMN; 0.0937; P < .0001) and Ser727 (0.586 & PLUSMN; 0.177 vs 0.886 & PLUSMN; 0.0546; P = .0157), which could be abolished by Stattic. CONCLUSIONS:DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the & alpha;2-adrenoreceptor in vivo and in vitro.

Automated summary

This study found that Dexmedetomidine (DEX) pretreatment can protect against myocardial ischemia/reperfusion injury (IRI) by promoting STAT3 phosphorylation. In both in vivo and in vitro experiments, DEX pretreatment reduced serum creatine kinase-MB isoenzyme (CK-MB) levels, suppressed inflammatory response, decreased cell apoptosis, and promoted STAT3 phosphorylation. These effects are believed to be mediated through the α2-adrenoreceptor and STAT3 signaling pathway.