Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.
Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.
复制标题
鉴定 Mtus1 剪接变体作为抗心脏肥大的新型抑制因子。
DOI：
10.1161/jaha.116.003521
复制
发表时间：
2016-07-06
影响因子：
5.4
通讯作者：
Kitakaze M
中科院分区：
文献类型：
--
作者：
Ito S;Asakura M;Liao Y;Min KD;Takahashi A;Shindo K;Yamazaki S;Tsukamoto O;Asanuma H;Mogi M;Horiuchi M;Asano Y;Sanada S;Minamino T;Takashima S;Mochizuki N;Kitakaze M
在心肌肥厚和心力衰竭中，mRNA剪接存在广泛的改变，但剪接变体在心肌肥厚中的作用尚未完全阐明。在这项研究中，我们使用外显子阵列来鉴定与心脏肥大相关的新型剪接变异体。我们进行了全基因组外显子阵列分析，并在横向主动脉缩窄诱导肥大的小鼠心脏中建立了剪接谱。在使用小鼠外显子1.0 ST阵列对剪接变体进行全局分析后，我们鉴定了46个剪接基因，并将我们的焦点缩小到1个基因，线粒体肿瘤抑制因子1（Mtus1），其剪接变体在NCBI RefSeq数据库中注册。值得注意的是，剪接变体之一Mtus1A被特异性上调，尽管Mtus1基因的总表达保持不变。我们发现Mtus 1A定位于线粒体中，并且其表达水平随着心脏肥大程度的增加而增加。在培养的心肌细胞中，Mtus1A过表达减少了苯肾上腺素诱导的活性氧产生和随后的ERK磷酸化，导致细胞大小和蛋白质合成减少。在体内，心脏特异性Mtus1A转基因小鼠显示左心室壁变薄，对压力超负荷和苯肾上腺素治疗的肥大反应降低。我们发现Mtus1在肥大心脏中特异性剪接，并且Mtus1A变体对心脏肥大具有抑制作用。因此，Mtus1A是心脏肥大和衰竭的可能诊断和治疗靶点。
In cardiac hypertrophy and failure, there is a widespread alteration in mRNA splicing, but the role of splice variants in cardiac hypertrophy has not yet been fully elucidated. In this study, we used an exon array to identify novel splice variants associated with cardiac hypertrophy. We performed genome‐wide exon array analysis and developed a splicing profile in murine hearts with hypertrophy induced by transverse aortic constriction for 8 weeks. Following global analysis of splice variants using the Mouse Exon 1.0 ST Array, we identified 46 spliced genes and narrowed our focus to 1 gene, mitochondrial tumor suppressor 1 (Mtus1), whose splice variants were registered in the NCBI RefSeq database. Notably, one of the splice variants Mtus1A was specifically upregulated, although the total expression of the Mtus1 gene remained unchanged. We showed that Mtus1A was localized in the mitochondria, and its expression level increased with the degree of cardiac hypertrophy. In cultured cardiomyocytes, Mtus1A overexpression reduced phenylephrine‐induced reactive oxygen species production and consequent ERK phosphorylation, resulting in a decrease in both cell size and protein synthesis. In vivo, cardiac‐specific Mtus1A transgenic mice showed left ventricle wall thinning and a reduced hypertrophic response to pressure overload and phenylephrine treatment. We found that Mtus1 is specifically spliced in hypertrophic hearts and that the Mtus1A variant has an inhibitory effect on cardiac hypertrophy. Mtus1A is, therefore, a possible diagnostic and therapeutic target for cardiac hypertrophy and failure.