Exercise Alleviates Atherosclerosis Progression through Regulation of Inflammatory Cytokines

Abstract

Atherosclerosis is one of the leading causes of mortality accounting for 30% of deaths worldwide. It is a disease of multifactorial etiology exemplified by lipid-driven inflammatory disease of the arterial intima. The atherosclerotic progression appears to be due to defective regulation of inflammatory events. Though exercise is conceived as a beneficial factor to combat many cardiovascular diseases, the effects of exercise on atherosclerosis progression under hyperlipidemic conditions and the precise mechanisms of exercise-induced plaque regression and stability remains unclear. Therefore, this study is to investigate the impact of exercise training on plaque formation and stability and regulation of inflammation in hyperlipidemia-induced atherosclerosis in ApoE-/- mice. Male ApoE-/- mice were randomly assigned to 3 groups (n = 6/group): Sedentary controls; pre-exercise and exercise groups and all fed with high fat diet (HFD) for 16 weeks. Pre-exercise group had exercise for 4 weeks with normal diet prior to HFD. Animals in pre-exercise and exercise groups were subjected to treadmill exercise for 60 min/day, 5 days/week at 15 m/min intensity with 5˚ slope for 16 weeks. After the scheduled exercise regime, the mice were sacrificed. Blood samples were collected for cytokine and lipid profile analyses, and aorta was harvested for en face Sudan IV staining. Image J software was used for lesion quantification. All groups of mice had total cholesterol levels over 400 mg/dl after 16 weeks of HFD (no significant difference among groups). Sudan IV staining of whole aorta revealed significant reductions of lesion in both exercise groups compared with sedentary controls. In sedentary controls, the total aorta lesion area was 33 ± 2.2 % after 16 weeks of HFD, while in pre-exercise and exercise groups, the mean lesion area was 24 ± 0.9 % and 27 ± 1.5 % of total aorta area, respectively, representing 28 and 19 % of lesion reduction relative to sedentary controls. The most lesion reduction occurred at arch and abdominal aorta and the reductions in pre-exercise group are more significant. This reduction in lesion is strikingly accompanied by reduction in major cytokines associated with atherosclerosis i.e. TNF-α, IL-1β, CRP and IFN-γ in pre-exercise and exercise groups. Though we see reduced cytokines in both exercise groups, pre-exercise showed more prominent response, indicating routine exercise prior to hyperlipidemia to have preventive effect on HFD-induced cytokine secretion. Pearson correlation analysis showed a significant positive correlation of reduction of lesion with IL-1β (r = 0.610, p< 0.01); TNF-α (r = 0.550, p<0.05) and IFN-γ (r = 0.470, p<0.05). Overall, our results indicated that exercise can significantly suppress the production of inflammatory cytokines and reduce lesion formation despite hyperlipidemic conditions. This study revealed a positive correlation between plasma pro-inflammatory cytokine levels and aorta lesion formation and provided underlying mechanisms by which sustained exercise training alleviates atherosclerosis progression under hyperlipidemic conditions.