Division of Cardiology, Department of Internal Medicine and Memorial Heart Center, Iwate Medical University School of Medicine, Iwate, Japan.
Clin Sci (Lond). 2012 Aug 1;123(3):161-71. doi: 10.1042/CS20110563.
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.
内皮细胞衰老被认为在 CAD（冠状动脉疾病）中起作用。miR-34a（microRNA-34a）和其他 SIRT1（沉默信息调节因子 1）相关的 miR 最近被发现靶向 SIRT1，导致内皮细胞衰老。在本研究中，我们研究了 miR-9、miR-34a、miR-132、miR-181a、miR-195、miR-199a、miR-199b 和 miR-204 等与 SIRT1 相关的 miR 是否在来自 CAD 患者的 EPCs（内皮祖细胞）中表达，以及他汀类药物（阿托伐他汀或瑞舒伐他汀）是否影响这些水平。为了确定 miR-34a 对 SIRT1 的影响，用 miR-34a 转染培养的 EPCs 分析总 SIRT1 蛋白水平。从 70 名 CAD 患者和 48 名无 CAD 患者中获得 EPCs。CAD 患者随机接受 8 个月的阿托伐他汀或瑞舒伐他汀治疗。在基线和他汀类药物治疗 8 个月后从外周血中获得 EPCs。通过实时 RT-PCR（逆转录-PCR）和 FACS 测量 EPCs 中的 miR 和 SIRT1 水平。miR-34a 的功能方法表明，miR-34a 转染到 EPCs 中导致 SIRT1 表达的调节。CAD 组的 miR-34a 水平高于非 CAD 组，而 CAD 组的 SIRT1 蛋白水平低于非 CAD 组。两组之间其他 miR（miR-9、miR-132、miR-181a、miR-195、miR-199a、miR-199b 和 miR-204）无显著差异。miR-34a 水平与 SIRT1 蛋白水平呈轻度负相关。一项随机临床试验表明，阿托伐他汀组的 miR-34a 水平显著降低，SIRT1 水平升高，而瑞舒伐他汀组的这些水平没有变化。阿托伐他汀和瑞舒伐他汀组的其他 miR 水平保持不变。总之，本研究的结果表明，miR-34a 可能在 EPCs 中调节 SIRT1 的表达，阿托伐他汀通过抑制 miR-34a 上调 SIRT1 的表达，这可能有助于阿托伐他汀对 CAD 内皮功能的有益作用。
