Acrolein-induced atherosclerosis via AMPK/SIRT1-CLOCK/BMAL1 pathway and the 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 h (from 0:00 to 18:00). We observed that IF reduced the formation of aortic lesions accelerated by acrolein in ApoE^−/− mice. Upon exposure to acrolein, there was an increase in RelA, Il1b, and Tnf levels in the liver and heart tissues, which were subsequently decreased by IF treatment. Notably, IF treatment upregulated the expression of adenosine monophosphate (AMP)-activated protein kinase catalytic subunit alpha-1 (AMPKα1), p-AMPKα1, and sirtuin 1 (SIRT1), while inhibiting acrolein-induced mitogen-activated protein kinase (MAPK) activation. Additionally, the expression of circadian genes Clock/Bmal1 was suppressed and disrupted by acrolein, while IF reversed this effect. Moreover, consistent with the in vivo findings, short-term starvation in vitro, as a fasting cell model, alleviated the dysregulation of CLOCK/BMAL1 and upregulated SIRT1 expression by modulating AMPK and reactive oxygen species (ROS)-MAPK pathways induced by acrolein. In summary, we demonstrated that IF suppressed the ROS-MAPK pathway but activated the AMPK pathway to enhance the expression of circadian clock genes, thereby ameliorating acrolein-induced atherogenesis, which may shed light on preventing cardiovascular diseases.