Work

Propofol in combination with salvianolic acid A protect against lipopolysaccharide-induced cardiac dysfunction and ferroptosis through activating the SIRT1/FoxO1 signaling under diabetic condition

Year: 2025

Type: article

Abstract: Background This study aimed to investigate the therapeutic potential of a combined low-dose propofol (PPF) and salvianolic acid A (SAA) regimen in mitigating lipopolysaccharide (LPS)-induced cardiac dysfunction and ferroptosis in diabetic contexts, and to explore the role of the sirtuin 1 (SIRT1)/forkhead box O1 (FoxO1) signaling pathway.Methods Type 2 diabetes (DM) was induced in mice, followed by LPS administration to induce cardiac injury. The mice were randomly assigned to six groups: control, DM, control + LPS, DM + LPS, DM + LPS + high-dose PPF, and DM + LPS + low-dose PPF + SAA. Cardiac function was assessed via echocardiography, while ferroptosis was evaluated with BODIPY staining and transmission electron microscopy. In vitro, H9c2 cardiomyocytes were treated with high glucose and LPS. Ferroptosis was assessed with FerroOrange and JC-1 staining. Oxidative stress and inflammatory cytokines were measured using ELISA or flow cytometry, and protein expression of key markers was analyzed.Results Diabetes aggravated LPS-induced cardiac injury in mice evidenced as impaired myocardial function, which was concomitant with decreased cardiac expression of SIRT1, FoxO1, and GPX4 proteins; increased production of oxidative stress, pro-inflammatory cytokines, oxidized lipids, and damaged mitochondrial cristae as compared to NC + LPS group. The combined use of PPF and SAA enhanced cardiac SIRT1 and FoxO1 and ameliorated LPS-mediated cardiac dysfunction in diabetic mice, but these beneficial effects were abolished by inhibition of SIRT1 or FoxO1. In vitro, hyperglycemia and LPS-induced cellular injuries were ameliorated by PPF and SAA, respectively. Low dose of PPF in combination with SAA reduced the production of ROS and ferroptosis that were concomitant with increased SIRT1 and FoxO1 expression, effects that were either comparable or superior to those achieved with high-dose PPF alone, but these protective effects were reversed by silencing SIRT1 or FoxO1.Conclusion The combination of low-dose PPF and SAA effectively protects against LPS-induced cardiac dysfunction and ferroptosis in diabetic conditions by activating the SIRT1/FoxO1 pathway.

Source: Annals of Medicine

DOI: 10.1080/07853890.2025.2570796