Sevoflurane Preconditioning Protects Against Myocardial Ischemia Reperfusion Injury in Mice via PI3K/AKT/GSK3β-mediated Upregulation of Syntaxin1a

Abstract

Preconditioning with volatile anesthetics, such as isoflurane and sevoflurane, can protect the myocardium against ischemia/reperfusion injury (IRI). Syntaxin1A (Stx1A) is cardioprotective and regulated by volatile anesthetics. However, is the mechanism by which sevoflurane preconditioning (SPC) induces Stx1A to exert myocardial protection remains unclear. The study investigates whether SPC induces upregulation of Stx1A through the thymoma viral proto-oncogene (AKT)/Glycogen synthase kinase 3 β (GSK3β) signaling pathway. Myocardial IRI model in mice was established by surgically ligating the left anterior descending coronary followed by loosening of the occlusion. Regulation of signaling pathway by intraperitoneal administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor, Ly294002 (30 mg/kg), and GSK3β inhibitor, TWS119 (30 mg/kg). The triphenyl tetrazolium chloride (TTC) staining method was used to measure the myocardial infarction area. Serum creatine kinase MB (CK-MB) and lactic dehydrogenase (LDH) concentration were measured by enzyme-linked immunosorbent assay (ELISA). Western blot was employed to examine AKT/GSK3β pathway activity, as well as expressions of Stx1A, small ubiquitin-like modifier 1 (SUMO1), growth hormone-releasing hormone (GHRH), or calcitonin gene-related peptide (CGRP), and brain natriuretic peptide (BNP). Both IRI and SPC induced upregulation of Stx1A in mice. However, the upregulation was abolished by treatment with Ly294002, while TWS119 further increased its expression (p < 0.05). Myocardial infarct area, serum CK-MB, and LDH were elevated in the IRI group but were inhibited by SPC-induced (p < 0.05); however, this inhibition by SPC was eliminated by Ly294002 (p < 0.05). TWS119 causes the opposite effect (p < 0.05). These findings demonstrated that SPC activated the AKT/GSK3β signaling pathway to upregulate Stx1A expression and provide protection to the myocardium.