Expression of let-7i is associated with Toll-like receptor 4 signal in coronary artery disease: Effect of statins on let-7i and Toll-like receptor 4 signal

Toll-like receptor (TLR) 4 signal plays an important role in immunity in coronary artery disease (CAD). A recent report has demonstrated that one of the let-7 family microRNAs, let-7i, directly regulates Toll-like receptor 4 (TLR4) expression and contributes to immune response. The aim of this study was to determine whether let-7i is expressed with TLR4 in patients with CAD, and whether statins (atorvastatin or rosuvastatin) might affect these levels. To determine the effects of let-7i on TLR4 expression, human THP-1 cells transfected with let-7i were analyzed for TLR4 levels. This study included 98 patients with CAD and 48 subjects without CAD (non-CAD). Patients with CAD were randomized to 12 months of treatment with atorvastatin or rosuvastatin. Monocytes were obtained from peripheral blood at baseline and after 12 months of each type of therapy. Levels of let-7i and TLR4 were measured by real-time RT-PCR and FACS. Functional approaches to let-7i showed that transfection of let-7i into human THP-1 cells resulted in regulation of TLR4 expression. Levels of let-7i were lower in the CAD group than in the non-CAD group (0.98 +/- 0.42 vs. 4.65 +/- 1.21, P < 0.01). There was a negative correlation between let-7i and TLR4 levels in patients with CAD (let-7i vs. TLR4 mRNA: r = -0.60, P < 0.01; let-7i vs. TLR4 MFI: r = -0.32, P < 0.01). The atorvastatin group had markedly increased let-7i levels and diminished TLR4 levels (all P < 0.01), whereas the rosuvastatin group showed no change in these levels. This study suggests that atorvastatin down-regulates TLR4 signal via let-7i expression in CAD patients, possibly contributing to the beneficial effects of atorvastatin on let-7i-mediated TLR4 signal in this disorder. (C) 2011 Elsevier GmbH. All rights reserved.