The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure

Tomohiko Ono, Naomi Kamimura, Tomohiro Matsuhashi, Toshihiro Nagai, Takahiko Nishiyama, Jin Endo, Takako Hishiki, Tsuyoshi Nakanishi, Noriaki Shimizu, Hirotoshi Tanaka, Shigeo Ohta, Makoto Suematsu, Masaki Ieda, Motoaki Sano, Keiichi Fukuda, Ruri Kaneda

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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.

Original languageEnglish
Article number39752
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 2017 Jan 4

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Methyltransferases
Histones
Lysine
Heart Failure
Salts
Diet
Inbred Dahl Rats
Mitochondrial Genes
Cardiomegaly
Gene Silencing
Acetylation
Methylation
Genes
Mitochondria
Animal Models
chaetocin
histone methyltransferase

ASJC Scopus subject areas

  • General

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The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure. / Ono, Tomohiko; Kamimura, Naomi; Matsuhashi, Tomohiro; Nagai, Toshihiro; Nishiyama, Takahiko; Endo, Jin; Hishiki, Takako; Nakanishi, Tsuyoshi; Shimizu, Noriaki; Tanaka, Hirotoshi; Ohta, Shigeo; Suematsu, Makoto; Ieda, Masaki; Sano, Motoaki; Fukuda, Keiichi; Kaneda, Ruri.

In: Scientific Reports, Vol. 7, 39752, 04.01.2017.

Research output: Contribution to journalArticle

Ono, T, Kamimura, N, Matsuhashi, T, Nagai, T, Nishiyama, T, Endo, J, Hishiki, T, Nakanishi, T, Shimizu, N, Tanaka, H, Ohta, S, Suematsu, M, Ieda, M, Sano, M, Fukuda, K & Kaneda, R 2017, 'The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure', Scientific Reports, vol. 7, 39752. https://doi.org/10.1038/srep39752
Ono, Tomohiko ; Kamimura, Naomi ; Matsuhashi, Tomohiro ; Nagai, Toshihiro ; Nishiyama, Takahiko ; Endo, Jin ; Hishiki, Takako ; Nakanishi, Tsuyoshi ; Shimizu, Noriaki ; Tanaka, Hirotoshi ; Ohta, Shigeo ; Suematsu, Makoto ; Ieda, Masaki ; Sano, Motoaki ; Fukuda, Keiichi ; Kaneda, Ruri. / The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure. In: Scientific Reports. 2017 ; Vol. 7.
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