title: The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure.
abstract: Histone acetylation has been linked to cardiac hypertrophy and heart failure. However, the pathological implications of changes in histone methylation and the effects of interventions with histone methyltransferase inhibitors for heart failure have not been fully clarified. Here, we focused on H3K9me3 status in the heart and investigated the effects of the histone H3K9 methyltransferase inhibitor chaetocin on prognoses in Dahl salt-sensitive rats, an animal model of chronic heart failure. Chaetocin prolonged survival and restored mitochondrial dysfunction. ChIP-seq analysis demonstrated that chronic stress to the heart induced H3K9me3 elevation in thousands of repetitive elements, including intronic regions of mitochondria-related genes, such as the gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Furthermore, chaetocin reversed this effect on these repetitive loci. These data suggested that excessive heterochromatinization of repetitive elements of mitochondrial genes in the failing heart may lead to the silencing of genes and impair heart function. Thus, chaetocin may be a potential therapeutic agent for chronic heart failure.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ono
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kamimura
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.affiliation: Electron Microscope Laboratory, Keio University Hospital, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nishiyama
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.|Clinical and Translational Research Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.|MS Business Unit, Shimadzu Corporation, Kyoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Division of Rheumatology, Center for Antibody and Vaccine Therapy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Division of Rheumatology, Center for Antibody and Vaccine Therapy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.|Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsukeshi, Tochigi, Japan.|JST, PRESTO, Kawaguchi, Saitama, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Kaneda
mesh_terms: D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000175:diagnosis* / Q000188:drug therapy; D002908:Chronic Disease; D004035:Diet Therapy; D006333:Heart Failure / Q000139:chemically induced / Q000175:diagnosis* / Q000188:drug therapy; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; C000620215:Ppargc1b protein, mouse; D010879:Piperazines; D034741:RNA, Small Interfering; D014157:Transcription Factors; C002511:chaetocin; D012965:Sodium Chloride; D011495:Histone-Lysine N-Methyltransferase