Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice

Hiromichi  Ueda; Osamu  Yamaguchi; Manabu  Taneike; Yasuhiro  Akazawa; Haruko  Wada-Kobayashi; Ryuta  Sugihara; Hiroki  Yorifuji; Hiroyuki  Nakayama; Shigemiki Omiya; Tomokazu Murakawa; Yasushi  Sakata; Kinya Otsu

doi:10.1016/j.jacbts.2019.01.002

Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice

Hiromichi Ueda, Osamu Yamaguchi, Manabu Taneike, Yasuhiro Akazawa, Haruko Wada-Kobayashi, Ryuta Sugihara, Hiroki Yorifuji, Hiroyuki Nakayama, Shigemiki Omiya, Tomokazu Murakawa, Yasushi Sakata, Kinya Otsu

Cardiovascular Sciences

Osaka University

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

122 Downloads (Pure)

Abstract

Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload–induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.

Original language	English
Article number	10
Pages (from-to)	348-363
Number of pages	16
Journal	JACC: Basic to Translational Science
Volume	4
Issue number	3
Early online date	22 May 2019
DOIs	https://doi.org/10.1016/j.jacbts.2019.01.002
Publication status	Published - Jun 2019

Keywords

Toll-like receptor 9
heart failure
mitochondria
pressure overload

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Administration of a TLR9_UEDA_Acc11Jan2019Epub22May2019_GOLD VoR(CC BY)Final published version, 3.75 MBLicence: CC BY

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Ueda, H., Yamaguchi, O., Taneike, M., Akazawa, Y., Wada-Kobayashi, H., Sugihara, R., Yorifuji, H., Nakayama, H., Omiya, S., Murakawa, T., Sakata, Y., & Otsu, K. (2019). Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice. JACC: Basic to Translational Science, 4(3), 348-363. Article 10. https://doi.org/10.1016/j.jacbts.2019.01.002

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title = "Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice",

abstract = "Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload–induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.",

keywords = "Toll-like receptor 9, heart failure, mitochondria, pressure overload",

author = "Hiromichi Ueda and Osamu Yamaguchi and Manabu Taneike and Yasuhiro Akazawa and Haruko Wada-Kobayashi and Ryuta Sugihara and Hiroki Yorifuji and Hiroyuki Nakayama and Shigemiki Omiya and Tomokazu Murakawa and Yasushi Sakata and Kinya Otsu",

year = "2019",

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doi = "10.1016/j.jacbts.2019.01.002",

language = "English",

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Ueda, H, Yamaguchi, O, Taneike, M, Akazawa, Y, Wada-Kobayashi, H, Sugihara, R, Yorifuji, H, Nakayama, H, Omiya, S , Murakawa, T, Sakata, Y & Otsu, K 2019, 'Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice', JACC: Basic to Translational Science, vol. 4, no. 3, 10, pp. 348-363. https://doi.org/10.1016/j.jacbts.2019.01.002

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T1 - Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice

AU - Ueda, Hiromichi

AU - Yamaguchi, Osamu

AU - Taneike, Manabu

AU - Akazawa, Yasuhiro

AU - Wada-Kobayashi, Haruko

AU - Sugihara, Ryuta

AU - Yorifuji, Hiroki

AU - Nakayama, Hiroyuki

AU - Omiya, Shigemiki

AU - Murakawa, Tomokazu

AU - Sakata, Yasushi

AU - Otsu, Kinya

PY - 2019/6

Y1 - 2019/6

N2 - Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload–induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.

AB - Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload–induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.

KW - Toll-like receptor 9

KW - heart failure

KW - mitochondria

KW - pressure overload

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DO - 10.1016/j.jacbts.2019.01.002

M3 - Article

SN - 2452-302X

VL - 4

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JO - JACC: Basic to Translational Science

JF - JACC: Basic to Translational Science

IS - 3

M1 - 10

ER -

Administration of a TLR9 inhibitor attenuates the development and progression of heart failure in mice

Abstract

Keywords

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