This study demonstrates that LLT with atorvastatin increases EPC numbers and decreases miR-221/222 levels in patients with CAD, possibly contributing to the beneficial effects of LLT with atorvastatin in this disorder.

Endothelial senescence is thought to play a role in CAD (coronary artery disease). miR-34a (microRNA-34a) and other SIRT1 (silent information regulator 1)-related miRs have recently been found to target SIRT1 leading to endothelial senescence. In the present study, we investigated whether SIRT1-related miRs, including miR-9, miR-34a, miR-132, miR-181a, miR-195, miR-199a, miR-199b and miR-204, and SIRT1 were expressed in EPCs (endothelial progenitor cells) obtained from patients with CAD, and whether statins (atorvastatin or rosuvastatin) affected these levels. To determine the effects of miR-34a on SIRT1, cultured EPCs transfected with miR-34a were analysed for total SIRT1 protein levels. EPCs were obtained from 70 patients with CAD and 48 subjects without CAD. Patients with CAD were randomized to 8 months of treatment with atorvastatin or rosuvastatin. EPCs were obtained from peripheral blood at baseline and after 8 months of statin therapy. Levels of miRs and SIRT1 in EPCs were measured by real-time RT–PCR (reverse transcription–PCR) and FACS. Functional approaches to miR-34a have shown that transfection of miR-34a into EPCs resulted in regulation of SIRT1 expression. Levels of miR-34a were higher in the CAD group than in the non-CAD group, whereas levels of SIRT1 protein were lower in the CAD group than in the non-CAD group. There were no significant differences in other miRs (miR-9, miR-132, miR-181a, miR-195, miR-199a, miR-199b and miR-204) between the two groups. Levels of miR-34a were mildly negatively correlated with SIRT1 protein levels. A randomized clinical study has shown that the atorvastatin group had markedly decreased miR-34a levels and increased SIRT1 levels, whereas the rosuvastatin group showed no change in these levels. Levels of other miRs remained unchanged in the atorvastatin and rosuvastatin groups. In conclusion the results of the present study suggest that miR-34a may regulate SIRT1 expression in EPCs and that atorvastatin up-regulates SIRT1 expression via inhibition of miR-34a, possibly contributing to the beneficial effects of atorvastatin on endothelial function in CAD.

The TLR4 (Toll-like receptor 4) signal plays an important role in immunity in CAD (coronary artery disease). miR-146a/b (where miR is microRNA) regulates the TLR4 downstream molecules IRAK1 (interleukin-1-receptor-associated kinase 1) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6). It has also been reported that statins and RAS (renin-angiotensin system) inhibition and have anti-atherosclerotic properties. In the present study, we have investigated whether miR-146a/b was expressed with the TLR4 signal in CAD patients, and whether combined treatment with a statin and RAS inhibition might affect these levels. A total of 66 patients with CAD and 33 subjects without CAD (non-CAD) were enrolled. Patients with CAD were randomized to 12 months of combined treatment with atorvastatin and telmisartan [an ARB (angiotensin II receptor blocker)] or atorvastatin and enalapril [an ACEI (angiotensin-converting enzyme inhibitor)]. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 12 months. Levels of miR-146a/b, IRAK1 mRNA, TRAF6 mRNA and TLR4 mRNA/TLR4 protein were significantly higher in the CAD group than in the non-CAD group (all P<0.01). Levels of miR-146a/b were positively correlated with IRAK1 mRNA and TRAF6 mRNA levels. After 12 months of treatment, these levels were markedly decreased in the ARB and ACEI groups, with the decrease in the ARB group being greater than that in the ACEI group (all P<0.05). In our 12-month follow-up study, high levels of miR-146a and TLR4 mRNA/TLR4 protein at baseline were independent predictors of cardiac events. The present study demonstrates that combined treatment with an ARB and a statin decreases miR-146a/b and the TLR4 signal in CAD patients, possibly contributing to the anti-atherogenic effects of ARBs and statins in this disorder.

No abstract

The NLRP-3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The aim of the present study was to determine whether NLRP3 inflammasome is expressed in patients with CAD (coronary artery disease) and whether statins (atorvastatin or rosuvastatin) might affect NLRP3 levels. In an in vitro study, human THP-1 cells treated with statins were analysed for NLRP3 inflammasome levels. The present study included 60 patients with CAD and 30 subjects without CAD (non-CAD). Patients with CAD randomly received either 8 months of treatment with atorvastatin or rosuvastatin. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 8 months of statin therapy. Levels of NLRP3 inflammasome, IL (interleukin)-1β and IL-18 were measured by real-time RT-PCR (reverse transcription-PCR) and FACS. Levels of NLRP3 inflammasome were higher in the CAD group than in the non-CAD group. There was a positive correlation between NLRP3 inflammasome and cytokines (IL-1β and IL-18) levels. A randomized clinical study has shown that atorvastatin markedly diminished NLRP3 inflammasome levels, whereas rosuvastatin had no impact on these levels. Levels of NLRP3 inflammasome decreased in THP-1 cells treated with statins compared with those treated with vehicle, and the fold changes in NLRP3 inflammasome were higher in THP-1 cells treated with atorvastatin compared with those treated with rosuvastatin. The present study suggests that atorvastatin down-regulates NLRP3 inflammasome expression in CAD, possibly contributing to the inhibitory effects of atorvastatin on chronic inflammation and atherogenic progression in this disorder.