title: Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.
abstract: 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.
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan masakura@ncvc.go.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Kyung-Duk
authors.initials: KD
authors.lastname: Min
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shindo
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Ehime, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Ehime, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C488664:Mtus1 protein, mouse; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins
keywords: cardiac hypertrophy; gene array; gene expression/regulation; molecular biology; splice variant