Canagliflozin Alleviates Atherosclerosis Progression through Inflammation, Oxidative Stress, and Autophagy in Western Diet-fed ApoE−/− Mice

Abstract

Purpose: This study was aimed at investigating the effect of canagliflozin (Cana) on atherosclerosis and further exploring its potential mechanism. Methods: ApoE−/− mice were fed a Western diet (WD) and randomly divided into a WD group and WD+Cana group. After 15 weeks of canagliflozin treatment, serum levels of fasting insulin and inflammatory cytokines were determined with ELISA kits. HE, Oil Red O, and Masson staining were used to estimate the extent of atherosclerosis. Immunohistochemistry, immunofluorescence, ROS staining, and RT-PCR were used to further investigate Cana’s potential mechanism. Results: Histological analysis indicated that Cana restrained atherosclerotic plaque development. Furthermore, Cana decreased the percentage of F4/80 positive cells, and the areal density of ROS and relative fluorescence intensity of P62, but enhanced the relative fluorescence intensity of LC3 in the aortic root. Analysis of factors associated with the inflammatory response mediated by AP-1, oxidative stress mediated through the ROS/Nrf2 pathway, and autophagy in the aorta indicated elevated mRNA levels of F4/80, MCP-1, VCAM-1, AP-1, ROS, NOX4, P62, NLRP3, and IL-1β, but diminished mRNA levels of Nrf2, GST, eNOS, and LC3, in the WD+Cana group. Conclusion: Canagliflozin may attenuate atherosclerosis by decreasing the inflammatory response mediated by AP-1, alleviating oxidative stress through the ROS/Nrf2 pathway, and enhancing autophagy in WD-fed ApoE−/− mice.