Author + information
- Received October 3, 2018
- Revision received January 10, 2019
- Accepted January 11, 2019
- Published online June 24, 2019.
- Hiromichi Ueda, MDa,
- Osamu Yamaguchi, MD, PhDa,
- Manabu Taneike, MD, PhDa,
- Yasuhiro Akazawa, MDa,
- Haruko Wada-Kobayashi, MDa,
- Ryuta Sugihara, MDa,
- Hiroki Yorifuji, MDa,
- Hiroyuki Nakayama, MD, PhDb,
- Shigemiki Omiya, MD, PhDc,
- Tomokazu Murakawa, MD, PhDc,
- Yasushi Sakata, MD, PhDa and
- Kinya Otsu, MD, PhDc,∗ ()
- aDepartment of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- bLaboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
- cSchool 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.
• Under pressure overload, mitochondrial deoxyribonucleic acid containing the unmethylated cytidine-phosphate-guanosine motif is accumulated in cardiomyocytes and stimulates Toll-like receptor 9, resulting in inflammation and heart failure.
• Treatment with E6446, (6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole), a specific Toll-like receptor 9 inhibitor, prevented the development and slowed the progression of left ventricular dilatation and cardiac dysfunction in mice after pressure overload.
• E6446 attenuated the inflammatory responses in the pressure-overloaded mouse heart, even though the accumulation of mitochondrial deoxyribonucleic acid in cardiomyocytes was observed.
• E6446 could be a new therapeutic agent against heart failure.
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.
This research was supported by the British Heart Foundation (CH/11/3/29051 and RG/16/15/32294), Fondation Leducq (RA15CVD04), and JSPS KAKENHI (18H02807), to Dr. Otsu. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received October 3, 2018.
- Revision received January 10, 2019.
- Accepted January 11, 2019.
- 2019 The Authors