1. Cardioprotective Effects of VCP Modulator KUS121 in Murine and Porcine Models of Myocardial Infarction
- Author
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Randolph Ruiz Rodriguez, Fumiko Nakazeki, Takeshi Kimura, Chiharu Otani, Yuya Ide, Sijia Xu, Takahiro Horie, Akira Kakizuka, Toshimitsu Watanabe, Koh Ono, Yui Miyasaka, Satoshi Koyama, Yasuhide Kuwabara, Naritatsu Saito, Masamichi Yamamoto, Tomohiro Nishino, Shin Watanabe, Yasuhiro Nakashima, Tomohiro Yamasaki, Masahiro Kimura, Hitoo Nishi, Motoko Yanagita, Masataka Nishiga, Shuhei Tsuji, and Tetsushi Nakao
- Subjects
0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,HF, heart failure ,PRECLINICAL RESEARCH ,0302 clinical medicine ,CMR, cardiac magnetic resonance ,Medicine ,LV, left ventricular/ventricle ,TTC, triphenyltetrazolium chloride ,Myocardial infarction ,I/R, ischemia and reperfusion ,FS, fractional shortening ,IHD, ischemic heart disease ,myocardial infarction ,H2O2, hydrogen peroxide ,MI, myocardial infarction ,Cardiology ,cardiovascular system ,AAR, area at risk ,ATPase, adenosine triphosphatase ,ER stress ,KUS121, Kyoto University Substance 121 ,Cardiology and Cardiovascular Medicine ,IBMPFD, inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia ,medicine.medical_specialty ,ATP, adenosine triphosphate ,Ischemia ,CHOP, C/EBP homologous protein ,FRET, fluorescence resonance energy transfer ,ER, endoplasmic reticulum ,03 medical and health sciences ,Reperfusion therapy ,Internal medicine ,KUS121 ,EF, ejection fraction ,cardiovascular diseases ,PCI, percutaneous coronary intervention ,business.industry ,Endoplasmic reticulum ,TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling ,BiP, immunoglobulin heavy chain-binding protein ,Percutaneous coronary intervention ,medicine.disease ,Infarct size ,ATP ,VCP, valosin-containing protein ,030104 developmental biology ,LAD, left anterior descending artery ,lcsh:RC666-701 ,Unfolded protein response ,business ,Reperfusion injury - Abstract
Visual Abstract, Highlights • 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., Summary 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.
- Published
- 2019