HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis.
HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis.
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DOI：
10.1161/circheartfailure.114.001781
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Menick DR
中科院分区：
文献类型：
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作者：
Renaud L;Harris LG;Mani SK;Kasiganesan H;Chou JC;Baicu CF;Van Laer A;Akerman AW;Stroud RE;Jones JA;Zile MR;Menick DR
microRNA（miRNAs）和组蛋白脱乙酰酶（HDAC）在多种心血管疾病的发病机制中起重要作用。在心肌肥厚中，miRNAs的转录调控机制知之甚少。我们研究了miR-133a的表达在肥厚性重塑过程中是否受I类和IIb类HDAC的表观遗传学调控。对CD 1小鼠进行横向主动脉缩窄（TAC）以诱导压力超负荷（PO）肥大。在TAC后2周和4周，通过饮用水用I类和IIb类HDAC抑制剂处理小鼠。通过真实的时间PCR测定miRNA表达。在基线和TAC后终点进行超声心动图，以进行结构和功能评估。染色质免疫沉淀（ChIP）用于鉴定与miR-133a启动子相关的HDAC和转录因子。与溶剂对照相比，TAC后2周和4周，miR-133 a表达分别下调0.7和0.5倍（P <0.05）。HDAC抑制防止了TAC后2周的这种显著降低，并将miR-133 a表达维持在接近媒介物对照水平，这与1）结缔组织生长因子（CTGF）表达的降低，2）心脏纤维化和左心房直径（舒张末期压的标志物）的降低相一致，表明舒张功能的改善。ChIP分析显示HDAC1和HDAC2存在于miR-133a增强子区域。结果表明，HDAC在PO诱导的miR-133a下调的调节中发挥作用。这项工作是第一个提供洞察PO诱导的心脏纤维化中的表观遗传-miRNA调控途径。
MicroRNAs (miRNAs) and histone deacetylases (HDACs) serve a significant role in the pathogenesis of a variety of cardiovascular diseases. The transcriptional regulation of miRNAs is poorly understood in cardiac hypertrophy. We investigated whether the expression of miR-133a is epigenetically regulated by Class I and IIb HDACs during hypertrophic remodeling. Transverse aortic constriction (TAC) was performed in CD1 mice to induce pressure overload (PO) hypertrophy. Mice were treated with Class I and IIb HDAC inhibitor via drinking water for 2 and 4 weeks post-TAC. miRNA expression was determined by real time PCR. Echocardiography was performed at baseline and post-TAC endpoints for structural and functional assessment. Chromatin immunoprecipitation (ChIP) was used to identify HDACs and transcription factors associated with miR-133a promoter. miR-133a expression was downregulated by 0.7 and 0.5 fold at 2 weeks and 4 weeks post-TAC respectively as compared to vehicle-control (P < 0.05). HDAC inhibition prevented this significant decrease 2 weeks post-TAC and maintained miR-133a expression near vehicle-control levels, which coincided with 1) a decrease in connective tissue growth factor (CTGF) expression, 2) a reduction in cardiac fibrosis and left atrium diameter (marker of end-diastolic pressure) suggesting an improvement in diastolic function. ChIP analysis revealed that HDAC1 and HDAC2 are present on the miR-133a enhancer regions. The results reveal that HDACs play a role in the regulation of PO-induced miR-133a downregulation. This work is the first to provide insight into an epigenetic-miRNA regulatory pathway in PO-induced cardiac fibrosis.