Cardioprotective Effects of VCP Modulator KUS121 in Murine and Porcine Models of Myocardial Infarction

[Display omitted] •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 suppr...

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Published in:JACC. Basic to translational science 2019-10, Vol.4 (6), p.701-714
Main Authors: Ide, Yuya, Horie, Takahiro, Saito, Naritatsu, Watanabe, Shin, Otani, Chiharu, Miyasaka, Yui, Kuwabara, Yasuhide, Nishino, Tomohiro, Nakao, Tetsushi, Nishiga, Masataka, Nishi, Hitoo, Nakashima, Yasuhiro, Nakazeki, Fumiko, Koyama, Satoshi, Kimura, Masahiro, Tsuji, Shuhei, Rodriguez, Randolph Ruiz, Xu, Sijia, Yamasaki, Tomohiro, Watanabe, Toshimitsu, Yamamoto, Masamichi, Yanagita, Motoko, Kimura, Takeshi, Kakizuka, Akira, Ono, Koh
Format: Article
Language:English
Subjects:
ATP
ER stress
KUS121
myocardial infarction
PRECLINICAL RESEARCH
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Summary:[Display omitted] •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.
ISSN:2452-302X
2452-302X
DOI:10.1016/j.jacbts.2019.06.001