Dataset Information

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

ABSTRACT:

Background

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.

Methods and results

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.

Conclusions

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.

SUBMITTER: Ito S

PROVIDER: S-EPMC5015389 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

Ito Shin S Asakura Masanori M Liao Yulin Y Min Kyung-Duk KD Takahashi Ayako A Shindo Kazuhiro K Yamazaki Satoru S Tsukamoto Osamu O Asanuma Hiroshi H Mogi Masaki M Horiuchi Masatsugu M Asano Yoshihiro Y Sanada Shoji S Minamino Tetsuo T Takashima Seiji S Mochizuki Naoki N Kitakaze Masafumi M

Journal of the American Heart Association 20160706 7

<h4>Background</h4>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.<h4>Methods and results</h4>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. Fo ...[more]

PMID: 27385424

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Project description:Expression of interleukins and their receptors is often regulated by alternative splicing. Alternative isoform of IL-5 receptor α-chain is well studied; however, no data on functional alternative splice variants of IL-5 has been reported up today. In the present study, we describe a novel splice variant for the mouse and human IL-5. The new form was found during analysis of PCR-products amplified from different mouse lymphoid tissues with a pair of primers designed to clone full-length mIL-5 ORF. A single short isoform of mIL-5 was detected along with the canonical full-length mRNA in ConA-stimulated lymphoid cells isolated from spleen, thymus, lymph nodes and blood. It was 30-40 nt shorter, and less abundant than classical form. The sequence analysis of an additional form of mIL-5 revealed that it lacks exon-2 (δ2). Using RT-PCR with the splice-specific primers we obtained an additional evidence for δ2 form expression. To verify whether mIL-5δ2 transcript is translated into protein, the coding sequences corresponding to full and δ2 forms of mIL-5 were cloned into an expression plasmid. After transfection into the human 293T cell line, we found that the short form of mIL-5 protein is expressed in cells and secreted into the supernatant, but at the reduced level than that detected for full isoform of mIL-5. Fluorescence microscopy examination revealed a partial translocation of mIL-5δ2 into cytoplasm, whereas mIL-5 resided mostly within endoplasmic reticulum. This can explain why the level of δ2 protein expression was reduced. Using a similar set of experimental approaches, we received the evidence that the human IL-5 mRNA has the δ2 splice form (hIL-5δ2) as well. It can be firmly detected by RT-PCR in PHA-activated mononuclear cells isolated from peripheral blood of healthy persons or patients with asthma. Altogether, our results showed that the human and mouse IL-5 have an alternative mRNA splice isoform, which loses exon-2, but nevertheless is expressed at protein level. However, more comprehensive studies will be required for evaluation of IL-5δ2 expression, regulation, biological function and clinical significance.

Dataset Information

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

Background

Methods and results

Conclusions

Publications

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

Similar Datasets

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