Author + information
- Received March 20, 2019
- Revision received June 12, 2019
- Accepted June 12, 2019
- Published online October 28, 2019.
- Yuya Ide, MDa,
- Takahiro Horie, MD, PhDa,
- Naritatsu Saito, MD, PhDa,
- Shin Watanabe, MD, PhDa,
- Chiharu Otani, MDa,
- Yui Miyasaka, BSca,
- Yasuhide Kuwabara, MD, PhDa,
- Tomohiro Nishino, MD, PhDa,
- Tetsushi Nakao, MD, PhDa,
- Masataka Nishiga, MD, PhDa,
- Hitoo Nishi, MD, PhDa,
- Yasuhiro Nakashima, MD, PhDa,
- Fumiko Nakazeki, MD, PhDa,
- Satoshi Koyama, MD, PhDa,
- Masahiro Kimura, MDa,
- Shuhei Tsuji, MDa,
- Randolph Ruiz Rodriguez, MDa,
- Sijia Xu, MDa,
- Tomohiro Yamasaki, MDa,
- Toshimitsu Watanabe, MDa,
- Masamichi Yamamoto, PhDb,
- Motoko Yanagita, MD, PhDb,c,
- Takeshi Kimura, MD, PhDa,
- Akira Kakizuka, MD, PhDd,∗∗ ( and )
- Koh Ono, MD, PhDa,∗ ()
- aDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
- bDepartment of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- cInstitute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
- dLaboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, Japan
- ↵∗Address for correspondence:
Dr. Koh Ono, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
- ↵∗∗Dr. Akira Kakizuka, Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto 606-8501, Japan.
• KUS121 was developed to selectively inhibit the adenosine triphosphatase activity of valosin-containing protein without affecting other cellular functions of valosin-containing protein.
• KUS121 preserved adenosine triphosphate levels, reduced endoplasmic reticulum stress, and suppressed cell death in H9C2 rat cardiomyoblast cells, treated with tunicamycin or hydrogen peroxide, or cultured in glucose-free medium.
• In murine ischemia and reperfusion injury models, KUS121 treatment after reperfusion attenuated the infarcted size and preserves cardiac function by maintaining adenosine triphosphate levels and reducing ER stress.
• In porcine ischemia and reperfusion injury models, intracoronary administration of KUS121 also attenuated the infarcted area in a dose-dependent manner.
• These results indicated that KUS121 is a promising novel therapeutic agent for myocardial infarction.
No effective treatment is yet available to reduce infarct size and improve clinical outcomes after acute myocardial infarction by enhancing early reperfusion therapy using primary percutaneous coronary intervention. The study showed that Kyoto University Substance 121 (KUS121) reduced endoplasmic reticulum stress, maintained adenosine triphosphate levels, and ameliorated the infarct size in a murine cardiac ischemia and reperfusion injury model. The study confirmed the cardioprotective effect of KUS121 in a porcine ischemia and reperfusion injury model. These findings confirmed that KUS121 is a promising novel therapeutic agent for myocardial infarction in conjunction with primary percutaneous coronary intervention.
This work was supported by Ministry of Education, Culture, Sports, Science and Technology and Japan Society for the Promotion of Science Grant Nos. 18K15888 (to Dr. Ide), 17K09860 (to Dr. Horie), JP1605297 (to Dr. Kimura), 16H05151 (to Dr. Kakizuka), and 17H04177 and 17H05599 (to Dr. Ono), and a visionary research grant (Step) from the Takeda Science Foundation (to Dr. Ono). In relation to this manuscript, Kyoto University has applied for a patent (Tokugan 2018-078272). Drs. Ide, Horie, Saito, Kimura, Kakizuka, and Ono are named as inventors on the patent. Dr. Kakizuka owns stock in Kyoto Drug Discovery and Development Co., Ltd., a start-up company for the development of VCP modulators. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The 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 March 20, 2019.
- Revision received June 12, 2019.
- Accepted June 12, 2019.
- 2019 The Authors