Abstract
Toll-like receptor 4 (TLR4)-tumor necrosis factor receptor 6 (TRAF6) signaling is
activated in atherosclerosis (AS), inducing inflammatory mediators. Because miR-146a,
a TLR4 microRNA (miRNA), can regulate TLR4 signaling during inflammatory responses,
this study investigated the effects of aerobic exercise on TLR4-targeted miRNAs in
AS. Apolipoprotein E-null mice fed a high-fat diet for 12 weeks were separated into
3 groups: (i) no treatment (AS), (ii) statin treatment (AD), or (iii) aerobic exercise
(AE). Plaques and foam cells were observed in the untreated control and statin groups,
respectively, but not in the AE group. Reduced angiotensin II (Ang II) and endothelin
1 (ET1) levels were observed in the AE group. Both treatment groups significantly
altered the expression of inflammatory cytokine expression and reduced vascular TLR4
levels. Increased miR-146a and miR-126 and reduced miR-155 levels were observed in
both treatment groups (all, P<0.001). miR-146a interacted with the 3′ untranslated
region of the TRAF6 gene, reducing its expression. Thus, aerobic exercise and statins may induce miR-146a
expression, thereby reducing vascular TRAF and TLR4 signaling and vascular inflammatory
injury in AS. Further analysis of this pathway may provide insight into the protective
effects of aerobic exercise on vascular disease as well as new therapeutic targets.
Key words
atherosclerosis - inflammation - TLR4 - miRNA