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

Yuya Ide; Takahiro Horie; Naritatsu Saito; Shin Watanabe; Chiharu Otani; Yui Miyasaka; Yasuhide Kuwabara; Tomohiro Nishino; Tetsushi Nakao; Masataka Nishiga; Hitoo Nishi; Yasuhiro Nakashima; Fumiko Nakazeki; Satoshi Koyama; Masahiro Kimura; Shuhei Tsuji; Randolph Ruiz Rodriguez; Sijia Xu; Tomohiro Yamasaki; Toshimitsu Watanabe; Masamichi Yamamoto; Motoko Yanagita; Takeshi Kimura; Akira Kakizuka; Koh Ono

doi:10.1016/j.jacbts.2019.06.001

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

JACC Basic Transl Sci. 2019 Oct 28;4(6):701-714. doi: 10.1016/j.jacbts.2019.06.001. eCollection 2019 Oct.

Authors

Yuya Ide¹, Takahiro Horie¹, Naritatsu Saito¹, Shin Watanabe¹, Chiharu Otani¹, Yui Miyasaka¹, Yasuhide Kuwabara¹, Tomohiro Nishino¹, Tetsushi Nakao¹, Masataka Nishiga¹, Hitoo Nishi¹, Yasuhiro Nakashima¹, Fumiko Nakazeki¹, Satoshi Koyama¹, Masahiro Kimura¹, Shuhei Tsuji¹, Randolph Ruiz Rodriguez¹, Sijia Xu¹, Tomohiro Yamasaki¹, Toshimitsu Watanabe¹, Masamichi Yamamoto², Motoko Yanagita^{2

3}, Takeshi Kimura¹, Akira Kakizuka⁴, Koh Ono¹

Affiliations

¹ Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
³ Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan.
⁴ Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto, Japan.

Abstract

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.

Keywords: AAR, area at risk; ATP; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; BiP, immunoglobulin heavy chain-binding protein; CHOP, C/EBP homologous protein; CMR, cardiac magnetic resonance; EF, ejection fraction; ER stress; ER, endoplasmic reticulum; FRET, fluorescence resonance energy transfer; FS, fractional shortening; H2O2, hydrogen peroxide; HF, heart failure; I/R, ischemia and reperfusion; IBMPFD, inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia; IHD, ischemic heart disease; KUS121; KUS121, Kyoto University Substance 121; LAD, left anterior descending artery; LV, left ventricular/ventricle; MI, myocardial infarction; PCI, percutaneous coronary intervention; TTC, triphenyltetrazolium chloride; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; VCP, valosin-containing protein; myocardial infarction.