Acrolein-induced atherosclerosis via AMPK/SIRT1-CLOCK/BMAL1 pathway and protection from intermittent fasting

The circadian clock is crucial for the progression of cardiovascular disease. Our previous studies showed that acrolein, an environmental pollutant, exacerbated atherosclerosis by reducing CLOCK/BMAL1 levels and disturbing circadian rhythm. In contrast, intermittent fasting (IF), a dietary regimen, ameliorated acrolein-induced atherosclerosis. In the current study, mice were administered acrolein at a dose of 3 mg/kg/day via their drinking water and subjected to IF for 18 hours (from 0:00 to 18:00). We observed that IF reduced the formation of aortic lesions in ApoE^−/− mice accelerated by acrolein. Upon exposure to acrolein, there was an increase in NF-κB, IL-1β, and TNF-α levels in the liver and heart tissues, which were subsequently decreased by IF treatment. Notably, IF treatment led to higher expression of AMPK, p-AMPK, and SIRT1, but lower MAPK levels, which were caused by acrolein. Additionally, the expression of circadian genes Clock/Bmal1 was suppressed and disturbed by acrolein, while IF reversed this effect. Moreover, consistent with that in vivo finding, short-term starvation in vitro, as a fasting cell model, improved the dysregulation of CLOCK/BMAL1 and increased SIRT1 expression by modulating AMPK and reactive oxygen species (ROS)-MAPK induced by acrolein. In summary, we demonstrated that IF suppressed ROS-MAPK but activated AMPK to enhance the expression of circadian clock genes, thereby ameliorating acrolein-induced atherogenesis, which may shed a light on preventing cardiovascular diseases.