The MEF2 transcriptional target DMPK induces loss of sarcomere structure and cardiomyopathy
The MEF2 transcriptional target DMPK induces loss of sarcomere structure and cardiomyopathy
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DOI：
10.1093/cvr/cvy091
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发表时间：
2018-09-01
影响因子：
10.8
通讯作者：
van Oort, Ralph J.
中科院分区：
文献类型：
--
作者：
Damanafshan, Amin;Elzenaar, Ies;van Oort, Ralph J.
目的 心力衰竭的病理学特征是心室收缩不良和扩张。在细胞水平上，这与单个心肌细胞的延长和肌节的丢失有关。虽然已知转录因子肌细胞增强因子-2 (MEF2) 参与这种心肌细胞重塑，但其潜在机制仍有待阐明。在这里，我们的目标是在机制上将MEF2靶基因与心肌细胞重塑过程中的肌节丢失联系起来。方法和结果过度表达MEF2的新生大鼠心肌细胞伸长并失去其肌节结构。我们确定强直性肌营养不良蛋白激酶 (DMPK) 是参与该过程的直接 MEF2 靶基因。 DMPK E（心力衰竭时上调的亚型）的腺病毒过度表达导致体外肌节严重丢失，而过度表达 DMPK E 的转基因小鼠在体内表现出肌节结构破坏和心肌病。此外，我们发现 DMPK E 功能获得后肌节基因的表达降低。这些基因是转录因子血清反应因子 (SRF) 的靶标，我们发现 DMPK E 充当 SRF 转录活性的抑制剂。结论我们的数据表明，MEF2 诱导的肌节丢失是由 DMPK 通过干扰 SRF 转录活性来减少肌节基因表达来介导的。总之，这些结果表明 DMPK 作为不良心肌细胞重塑和心力衰竭的直接介质具有意想不到的作用。
Aims The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor-2 (MEF2) is involved in this cardiomyocyte remodelling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodelling.Methods and results Neonatal rat cardiomyocytes overexpressing MEF2 elongated and lost their sarcomeric structure. We identified myotonic dystrophy protein kinase (DMPK) as direct MEF2 target gene involved in this process. Adenoviral overexpression of DMPK E, the isoform upregulated in heart failure, resulted in severe loss of sarcomeres in vitro, and transgenic mice overexpressing DMPK E displayed disruption of sarcomere structure and cardiomyopathy in vivo. Moreover, we found a decreased expression of sarcomeric genes following DMPK E gain-of-function. These genes are targets of the transcription factor serum response factor (SRF) and we found that DMPK E acts as inhibitor of SRF transcriptional activity.Conclusion Our data indicate that MEF2-induced loss of sarcomeres is mediated by DMPK via a decrease in sarcomeric gene expression by interfering with SRF transcriptional activity. Together, these results demonstrate an unexpected role for DMPK as a direct mediator of adverse cardiomyocyte remodelling and heart failure.