Dept. of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL, USA.
J Mol Cell Cardiol. 2013 Dec;65:59-66. doi: 10.1016/j.yjmcc.2013.09.012. Epub 2013 Sep 29.
Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in genes encoding sarcomeric proteins. One of the most frequent affected genes is MYBPC3, which encodes the thick filament protein cardiac myosin binding protein C. Despite the prevalence of HCM, disease pathology and clinical outcome of sarcomeric mutations are largely unknown. We hypothesized that microRNAs (miRNAs) could play a role in the disease process. To determine which miRNAs were changed in expression, miRNA arrays were performed on heart tissue from HCM patients with a MYBPC3 mutation (n=6) and compared with hearts of non-failing donors (n=6). 532 out of 664 analyzed miRNAs were expressed in at least one heart sample. 13 miRNAs were differentially expressed in HCM compared with donors (at p<0.01, fold change ≥ 2). The genomic context of these differentially expressed miRNAs revealed that miR-204 (fold change 2.4 in HCM vs. donor) was located in an intron of the TRPM3 gene, encoding an aspecific cation channel involved in calcium entry. RT-PCR analysis revealed a trend towards TRPM3 upregulation in HCM compared with donor myocardium (fold change 2.3, p=0.078). In silico identification of mRNA targets of differentially expressed miRNAs showed a large proportion of genes involved in cardiac hypertrophy and cardiac beta-adrenergic receptor signaling and we showed reduced phosphorylation of cardiac troponin I in the HCM myocardium when compared with donor. HCM patients with MYBPC3 mutations have a specific miRNA expression profile. Downstream mRNA targets reveal possible involvement in cardiac signaling pathways.
肥厚型心肌病（HCM）主要由编码肌节蛋白的基因突变引起。受影响最频繁的基因之一是编码心肌球蛋白结合蛋白 C 的厚丝蛋白基因 MYBPC3。尽管 HCM 很常见，但肌节突变的疾病病理学和临床结果在很大程度上尚不清楚。我们假设 microRNAs（miRNAs）可能在疾病过程中发挥作用。为了确定表达谱中哪些 miRNAs 发生了变化，我们对 HCM 患者（n=6）的 MYBPC3 突变心肌组织和非衰竭供体的心肌组织（n=6）进行了 miRNA 芯片分析。在至少一个心脏样本中表达了 664 个分析的 miRNAs 中的 532 个。与供体相比，HCM 中有 13 个 miRNA 表达差异（p<0.01，倍数变化≥2）。这些差异表达 miRNA 的基因组背景表明，miR-204（在 HCM 中与供体相比倍数变化 2.4）位于编码参与钙内流的非特异性阳离子通道的 TRPM3 基因的内含子中。RT-PCR 分析显示与供体心肌相比，HCM 中 TRPM3 有上调趋势（倍数变化 2.3，p=0.078）。差异表达 miRNA 的 mRNA 靶标鉴定表明，涉及心脏肥大和心脏β肾上腺素能受体信号的基因比例很大，并且我们发现与供体相比，HCM 心肌中的心肌钙蛋白 I 磷酸化减少。携带 MYBPC3 突变的 HCM 患者具有特定的 miRNA 表达谱。下游 mRNA 靶标表明可能参与心脏信号通路。
