Division of Cardiology, Department of Internal Medicine and Memorial Heart Center, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka 020-8505, Iwate, Japan.
Clin Sci (Lond). 2010 Jul 23;119(9):395-405. doi: 10.1042/CS20100003.
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.
TLR4（Toll 样受体 4）信号在 CAD（冠状动脉疾病）中的免疫中发挥重要作用。miR-146a/b（miR 是 microRNA）调节 TLR4 下游分子 IRAK1（白细胞介素-1 受体相关激酶 1）和 TRAF6（肿瘤坏死因子受体相关因子 6）。据报道，他汀类药物和 RAS（肾素-血管紧张素系统）抑制具有抗动脉粥样硬化作用。在本研究中，我们研究了 CAD 患者中 TLR4 信号是否与 miR-146a/b 表达相关，以及他汀类药物和 RAS 抑制的联合治疗是否可能影响这些水平。共纳入 66 例 CAD 患者和 33 例非 CAD 患者（非 CAD）。CAD 患者随机分为阿托伐他汀联合替米沙坦（ARB）或阿托伐他汀联合依那普利（ACEI）治疗 12 个月。从外周血获得 PBMC（外周血单核细胞）在基线和 12 个月后。与非 CAD 组相比，CAD 组的 miR-146a/b、IRAK1 mRNA、TRAF6 mRNA 和 TLR4 mRNA/TLR4 蛋白水平显着升高（均 P<0.01）。miR-146a/b 水平与 IRAK1 mRNA 和 TRAF6 mRNA 水平呈正相关。经过 12 个月的治疗，ARB 和 ACEI 组这些水平显着下降，ARB 组下降幅度大于 ACEI 组（均 P<0.05）。在我们为期 12 个月的随访研究中，基线时高 miR-146a 和 TLR4 mRNA/TLR4 蛋白水平是心脏事件的独立预测因子。本研究表明，ARB 和他汀类药物的联合治疗可降低 CAD 患者的 miR-146a/b 和 TLR4 信号，可能有助于 ARB 和他汀类药物在该疾病中的抗动脉粥样硬化作用。
