State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing, 100037, People's Republic of China.
J Transl Med. 2018 Jun 9;16(1):161. doi: 10.1186/s12967-018-1534-3.
MicroRNAs (miRNAs) are non-coding RNAs that function as regulators of gene expression and thereby contribute to the complex disease phenotypes. Hypertrophic cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM) can cause sudden cardiac death and eventually develop into heart failure. However, they have different clinical and pathophysiological phenotype and the expressional spectrum of miRNAs in left ventricles of HCM and DCM has never been compared before.
This study selected 30 human left ventricular heart samples belonged to three diagnostic groups (Control, HCM, DCM). Each group has ten samples. Based on previous findings, the expression of 13 different microRNAs involving heart failure and hypertrophy (miR-1-3p, miR-10b, miR-21, miR-23a, miR-27a, miR-29a, miR-133a-3p, miR-142-3p, miR-155, miR-199a-3p, miR-199a-5p, miR-214, miR-497) was measured. 17 HCM patients were included as second group to validate the associations.
We found miR-155, miR-10b and miR-23a were highly expressed in both HCM and DCM compared with control. MiR-214 was downregulated and miR-21 was upregulated in DCM but not in HCM. We also identified miR-1-3p and miR-27a expressed significantly different between HCM and DCM and both miRNAs downregulated in HCM. And only miR-1-3p correlated with left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) that reflected the cardiac function in HCM. A second HCM group also confirmed this correlation. We then predicted Chloride voltage-gated channel 3 (Clcn3) as a direct target gene of miR-1-3p using bioinformatics tools and confirmed it by Luciferase reporter assay.
Our data demonstrated that different cardiomyopathies had unique miRNA expression pattern. And the expression levels of miR-1-3p and miR-27a had disease-specificity and sensitivity in HCM, whereas only miR-1-3p was significantly associated with left ventricular function in HCM identifying it as a potential target to improve the cardiac function in end-stage HCM. We also provide Clcn3 as a direct target of miR-1-3p which sheds light on the mechanism of HCM.
MicroRNAs（miRNAs）是非编码 RNA，作为基因表达的调节剂，从而有助于复杂的疾病表型。肥厚型心肌病（HCM）和扩张型心肌病（DCM）可导致心源性猝死，并最终发展为心力衰竭。然而，它们具有不同的临床和病理生理表型，并且 HCM 和 DCM 左心室中的 miRNA 表达谱从未进行过比较。
本研究选择了 30 个人类左心室心脏样本，属于三个诊断组（对照组、HCM、DCM）。每个组有十个样本。基于先前的发现，测量了涉及心力衰竭和肥大的 13 种不同 miRNA 的表达（miR-1-3p、miR-10b、miR-21、miR-23a、miR-27a、miR-29a、miR-133a-3p、miR-142-3p、miR-155、miR-199a-3p、miR-199a-5p、miR-214、miR-497）。纳入了 17 名 HCM 患者作为第二组来验证相关性。
我们发现与对照组相比，miR-155、miR-10b 和 miR-23a 在 HCM 和 DCM 中均高度表达。miR-214 在 DCM 中下调，而在 HCM 中未下调。我们还发现 miR-1-3p 和 miR-27a 在 HCM 和 DCM 之间表达显著不同，并且两种 miRNA 在 HCM 中下调。只有 miR-1-3p 与 HCM 中的左心室舒张末期直径（LVEDD）和左心室射血分数（LVEF）相关，这反映了 HCM 中的心脏功能。第二组 HCM 也证实了这种相关性。然后，我们使用生物信息学工具预测氯离子电压门控通道 3（Clcn3）为 miR-1-3p 的直接靶基因，并通过荧光素酶报告基因检测进行了验证。
我们的数据表明，不同的心肌病具有独特的 miRNA 表达模式。miR-1-3p 和 miR-27a 在 HCM 中具有疾病特异性和敏感性，而只有 miR-1-3p 与 HCM 中的左心室功能显著相关，将其确定为改善终末期 HCM 心脏功能的潜在靶点。我们还提供了 Clcn3 作为 miR-1-3p 的直接靶基因，这为 HCM 的发病机制提供了线索。
