Curcumin attenuates heatstroke-induced myocardial injury and ventricular arrhythmias by regulating the BAX/BCL-2/caspase-3 pathway

Abstract

Background: heatstroke (HS) is characterized by a high incidence of cardiac injury and multiple complications, with no specific therapeutic agents available. Curcumin (CUR) has demonstrated cardioprotective effects, but its role in HS-induced myocardial injury and arrhythmias remains poorly understood. Objective: this study aims to examine the protective effects of CUR in HS-induced myocardial injury and ventricular arrhythmias and elucidate its mechanism via the BAX/BCL-2/caspase-3 apoptotic pathway. Materials and methods: a rat model of HS was established, consisting of three groups: control (CT) group, HS group, and CUR intervention (HS + CUR) group. Myocardial injury markers were assessed using enzyme-linked immunosorbent assays (ELISAs). Electrophysiological parameters were evaluated utilizing electrocardiography (ECG), electrophysiological examination, a rechargeable animal telemetry system, and a microelectrode array (MEA). Echocardiography and pressure–volume (PV) loop assessment were performed to evaluate changes in cardiac function. Histological alterations in myocardial tissue were examined through hematoxylin–eosin (HE) and wheat germ agglutinin (WGA) staining. Cardiac ultrastructure was observed via transmission electron microscopy (TEM). Integration of transcriptomics, proteomics, and network pharmacology facilitated the identification of the common targets of HS and CUR, followed by gene set variation analysis (GSVA). Molecular docking and molecular dynamics simulations confirmed the interaction of CUR with BAX, BCL-2, and caspase-3. Apoptosis was examined utilizing cell counting kit-8 (CCK-8) assay, Hoechst and TUNEL staining, flow cytometry, and western blotting (WB) in vivo and in vitro. Results: the HS group showed elevated body temperature, reduced weight, lower survival, increased myocardial injury markers, and ventricular electrical/structural remodeling. CUR treatment ameliorated these effects. Multi-omics identified 18 differential molecules and two common targets (Serpine1 and Hspa8). Molecular docking confirmed the stable binding of CUR to BAX/BCL-2/caspase-3. In vivo/in vitro experiments showed that CUR inhibited HS-induced cell apoptosis. Conclusion: CUR exhibits protective effects against HS-induced myocardial damage and decreases susceptibility to ventricular arrhythmias in HS rats and inhibits HS-induced injury in H9C2 cells. Its mechanism to improve myocardial injury and ventricular arrhythmias may involve inhibition of the BAX/BCL-2/caspase-3 pathway.