Dexmedetomidine Preconditioning Protects Isolated Rat Hearts with Hyperglycemia Against Ischemia/Reperfusion Injury through PI3K/AKT signaling pathway

Abstract Background Dexmedetomidine (Dex) has myocardial protective effects, but fewer researches focus on the cardioprotection of dexmedetomidine in high glucose environment. The purpose of this research was to unveil this protective effect and mechanism of Dex preconditioning against ischemia/reperfusion(I/R) injury of hearts and H2O2-induced cardiomyocyte apoptosis with hyperglycemia. Methods Langendorff model was established. Test groups were pretreated with dexmedetomidine for 30 min and washed out for 10 min, subsequently exposed to 30 min of ischemia and 60 min of reperfusion. We randomly separated isolated hearts to seven groups. Furthermore, the perfusate of Krebs-Henseleit buffer (KHB) in experimental groups contained 33 mM glucose, while the glucose concentration in control group was 11 mM. Left ventricular developed pressure, +dp/dtmax, -dp/dtmax, heart rates as well as high-sensitivity cardiac troponin T(hs-cTnT) of coronary perfusion were assessed. Triphenyl tetrazolium chloride staining was used to test infarct size at last. To explore the mechanism of Dex protective effect, H9C2 cardiomyocytes were pretreated with or without 10 nM Dex and PI3K inhibitor LY294002 before being exposed to H2O2 to induce oxidative cellular damage in low or high glucose culture medium. Cell viability, apoptosis ratio and protein expressions were detected by CCK8, TUNEL, flow cytometry and Western blot. Results After 33mM glucose-KHS treatment and global ischemia/reperfusion, left ventricular function indexes of the isolated hearts in I/R group were significantly reduced (p < 0.001), nonetheless infarct sizes of the left ventricle and hs-cTnT (p < 0.001) were obviously increased. Dexmedetomidine preconditioning reduced I/R-induced left ventricular dysfunction and left ventricle infarct size (p < 0.001). hs-cTnT was lower in rat hearts preconditioned with Dex (p < 0.001). Moreover, the myocardial protective effects of Dex in high glucose perfusate were not related to osmotic pressure changes. H2O2 significantly decreased cell viability and increased necroptotic and apoptotic cell deaths in high glucose culture medium group (p < 0.01, HG + H2O2 vs. Control). Dex prevented H2O2‑induced cardiomyocyte apoptosis through PI3K/AKT signaling pathway under high glucose circumstances, for it significantly decreased expressions of proteins caspase 3, Bax and increased expressions of proteins Bcl-2, p-PI3K and p-AKT. While all these protective effects of Dex were reversed by LY294002 (p < 0.01, HG + H2O2 vs. HG + DP + H2O2 and LY294002 + HG + DP + H2O2 vs. HG + DP + H2O2). These findings indicated that Dex attenuates H2O2-induced cardiomyocyte apoptotic cell death through PI3K/AKT signaling pathway under high glucose circumstances. Conclusions Acute hyperglycemia exacerbates myocardial I/R injury but dexmedetomidine attenuates myocardial I/R injury and H2O2-induced cardiomyocyte apoptosis through PI3K/AKT signaling pathway.