Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice

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

JACC: Basic to Translational Science (Jun 2019)

Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice

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

Affiliations

Hiromichi Ueda, MD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Osamu Yamaguchi, MD, PhD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Manabu Taneike, MD, PhD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Yasuhiro Akazawa, MD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Haruko Wada-Kobayashi, MD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Ryuta Sugihara, MD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Hiroki Yorifuji, MD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Hiroyuki Nakayama, MD, PhD: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
Shigemiki Omiya, MD, PhD: School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
Tomokazu Murakawa, MD, PhD: School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
Yasushi Sakata, MD, PhD: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Kinya Otsu, MD, PhD: School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom; Address for correspondence: Dr. Kinya Otsu, School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London SE5 9NU, United Kingdom.

Journal volume & issue: Vol. 4, no. 3
pp. 348 – 363

Abstract

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Summary: 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. Key Words: heart failure, mitochondria, pressure overload, Toll-like receptor 9

Published in JACC: Basic to Translational Science

ISSN: 2452-302X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.journals.elsevier.com/jacc-basic-to-translational-science/

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