ApoE−/− mice (male, C57BL/6 background, 5 weeks old) were provided by Shanghai Model Organisms Center, Inc. (Shanghai, China) and kept in microisolator cages with water and food available ad libitum, under specific pathogen-free conditions at the Shanghai Model Organisms Center. ApoE−/− mice were fed a western diet (21% fat, 0.15% cholesterol; SLAC, Shanghai, China) (Liu et al., 2013 (link)) from 5 weeks of age, and samples were collected at 6, 8, 11, 14, and 18 weeks of age (5 mice per group) to determine the timepoint and duration of pharmacological intervention. Thirty-six 5-week-old ApoE−/− mice were also fed the western diet, and at 14 weeks of age these mice were randomized into four groups. Treatments were administered to the four groups via intraperitoneal injection for 4 weeks, as follows: 1) control (vehicle, 0.25 mL, 2% DMSO/day), 2) Z-YVAD-FMK (Fu et al., 2019 (link)) (0.25 mL, 200 μg/day), 3) Z-LLSD-FMK (0.25 mL, 200 μg/day), and 4) Z-YVAD-FMK + Z-LLSD-FMK (0.25 mL, 200 μg + 200 μg/day). Mice were killed at 18 weeks of age. All mouse studies were approved by the Animal Ethics Committee of Zhongshan Hospital, Fudan University. All experimental procedures were performed in accordance with the guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) (Zhang et al., 2021 (link)).
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