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

Autor: 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, Tetsushi Nakao
Jazyk: angličtina
Rok vydání: 2019
Předmět:
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
Zdroj: JACC: Basic to Translational Science, Vol 4, Iss 6, Pp 701-714 (2019)
JACC: Basic to Translational Science
Popis: 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.
Databáze: OpenAIRE
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