Exercise training-induced plaque stabilization in rabbits associated with restored β-adrenergic receptor signaling and reduced ectopic trypsin.

Abstract

BACKGROUND AND AIMS: Our previous research confirmed the abundant expression of ectopic trypsin in coronary and aortic atherosclerotic plaques, and its inhibition enhances plaque stability. Given the established benefits of physical activity in cardiovascular disease prevention, this study aimed to investigate whether exercise-induced plaque stabilization associates with the β-adrenergic receptor (β-AR) signaling pathway and ectopic trypsin expression. METHODS: Twenty-four male New Zealand rabbits were randomly assigned to three groups (n = 8 per group): a control group (Group C, standard diet), an atherosclerosis group (Group A, high-fat/high-cholesterol diet), and an exercise group (Group E, high-fat/high-cholesterol diet + exercise training from week 12 to 16). At the end of the study, serum lipid profiles were analyzed. The aortas and hearts containing the coronary arteries were harvested for pathological and biochemical analyses. RESULTS: Compared with coronary and aortic intima tissues in Group C, atherosclerotic plaque tissues in Group A exhibited significantly reduced levels of β-AR and its downstream signaling components, including adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-PKA (P-PKA) and β-arrestin2. Furthermore, the ratio of P-PKA to PKA was also significantly decreased in Group A. Conversely, the expression of nuclear factor κB (NF-κB), trypsin, protease-activated receptor-2 (PAR-2), matrix metalloproteinase-9 (MMP-9), and the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)α was significantly higher in Group A than in Group C. Exercise training in Group E effectively counteracted high-fat diet induced suppression of the β-AR signaling pathway and up-regulation of NF-κB, resulting in inhibition of trypsin, PAR-2, and MMP-9, reduced pro-inflammatory cytokines, and increased fibrous cap thickness. CONCLUSIONS: Stabilization of atherosclerotic plaques by exercise training is associated with restoration of the β-AR signaling and inhibition of ectopic trypsin expression, providing a potent preventive strategy for acute coronary syndrome.