Section of Cardiology, Department of Medicine, University of Illinois at Chicago and the Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
Trends Cardiovasc Med. 2013 Jan;23(1):5-8. doi: 10.1016/j.tcm.2012.08.003. Epub 2012 Aug 31.
Alternative splicing is a posttranscriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure (HF), we found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF. Our results show that angiotensin II and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na(+) current. These observations may shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na(+) channel blocking anti-arrhythmic drug complications.
选择性剪接是一种转录后机制，可以显著改变基因表达模式。多达 95%的人类基因具有多外显子的选择性剪接形式，这表明选择性剪接是人类基因组功能复杂性的最重要组成部分之一。然而，在心脏疾病的研究中，选择性剪接调控受到的关注相对较少。当我们在心力衰竭 (HF) 中研究 SCN5A 剪接异常时，发现与对照组相比，HF 中有 181 个已知剪接调控因子中的 47 个上调，这表明剪接调控可能在 HF 中发挥关键作用。我们的结果表明，血管紧张素 II 和缺氧，HF 常见的信号，导致 LUC7L3 和 RBM25 剪接调控因子增加，RBM25 与 SCN5A mRNA 的结合增加，SCN5A 剪接变异体丰度增加，全长 SCN5A mRNA 和蛋白减少，以及 Na(+)电流减少。这些观察结果可能揭示了一种机制，通过该机制，心脏功能和心律失常风险相关联，并允许更精细地预测哪些患者可能具有最高的心律失常风险或患有 Na(+)通道阻断抗心律失常药物并发症。
