P838
Expression of miR-23a induces leukocyte telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease

Extract

Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance. MicroRNA (miR)-23a may directly inhibit TRF2 expression, inducing telomere shortening and cellular senescence. This study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels.

This study included 104 patients with CAD and 50 controls. Patients with CAD were randomized to 12 months of treatment in either a moderate lipid lowering therapy (LLT) group (pitavastatin 1mg / day) or an aggressive LLT group (pitavastatin 4 mg / day). Circulating leukocytes were obtained from peripheral blood at baseline and after 12 months. Levels of miR-23a measured using real-time RT-PCR. Levels of TRF2 protein analyzed by flow cytometer. Relative telomere length (RTL) of lymphocyte also measured using flow FISH method.

Levels of miR-23a were higher in the CAD group than in the controls (P<0.01), whereas levels of TRF2 protein were lower in the CAD group than in the controls (P<0.01). RTL was significantly lower in the CAD group than in the control group (P<0.01). Our randomized clinical study showed that aggressive LLT markedly decreased levels of miR-23a (2.78±1.29 vs. 2.09±1.17, P<0.01) and increased levels of TRF2 (2.67±1.36 vs. 3.16±1.46, P<0.01), whereas moderate LLT had no impact on levels of miR-23a (2.75±0.98 vs. 2.47±1.29, not significant) or TRF2 (2.79±1.34 vs. 2.82±1.29, not significant). Our functional approaches showed that transfection of miR-23a into isolated leukocytes resulted in regulation of TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a, low TRF2 or low RTL (all P<0.05). Multivariate analysis showed that levels of miR-23a (RR 5.2, 95% CI 2.0–15.5) were a strong predictor of cardiovascular events after adjustment for baseline characteristics.