Sestrin1 mediates the anti-inflammatory effects of aerobic exercise in atherosclerosis

Atherosclerosis (AS) is a major contributor to cardiovascular and cerebrovascular disorders. Although aerobic exercise is widely regarded as a beneficial non-pharmacological therapy, the specific molecular basis for its protective effects remains incompletely defined. Sestrin proteins are a conserved family of proteins, and sestrin 1 (SESN1) has been associated with both AS pathologies and exercise-related physiological effects. Clarifying how SESN1 contributes to exercise-induced protective effects may enhance understanding of exercise-based cardiovascular rehabilitation.

This study examined the involvement of SESN1 and its regulatory mechanism in exercise-mediated modulation of inflammatory activity in AS.

After establishing the AS mouse model, three experimental groups were generated: "AS mice", "exercise + AS mice", and "exercise + SESN1^-/- AS mice" (SESN1 silence). Then all groups underwent an 8-week treadmill protocol except for the "AS mice" group. Levels of interleukin (IL-18, IL-6), matrix metalloproteinases (MMPs), and central components of the SESN1-AMPK-mTORC-nuclear factor-κB (NF-κB) pathway were quantified using ELISA, quantitative Real-Time PCR (qRT-PCR), and Western blot.

Aerobic exercise markedly increased SESN1 expression and suppressed inflammatory indicators. SESN1 knockdown diminished these beneficial effects, resulting in persistent inflammation. Mechanistically, exercise promoted AMPK phosphorylation, leading to downregulation of mTORC activation and NF-κB activation in a manner partly dependent on SESN1, thereby inhibiting inflammatory responses.

SESN1 protein's expression was up-regulated after exercise intervention in AS mice, partially functioning as a mediator of the exercise-induced anti-inflammatory response in AS through the AMPK-mTORC-NF-κB axis.