Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury.
The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.|Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hui
H
Liu
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.|Department of Anaesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lei
L
Yang
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Hui-Jun
HJ
Wu
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.|Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Kui-Hao
KH
Chen
Shanghai Institute of Pharmaceutical Industry, China National Pharmaceutical Group, Shanghai, China.
Feng
F
Lin
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.|Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, China.
Gang
G
Li
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Hai-Ying
HY
Sun
Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, China.
Guo-Sheng
GS
Xiao
Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, China.
Yan
Y
Wang
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.|Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, China.
Gui-Rong
GR
Li
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D047309:Flavones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects; D000099156:Superoxide Dismutase 2
D047309:Flavones; D015850:Interleukin-6; D011355:Prodrugs; D020011:Protective Agents; D013482:Superoxide Dismutase; D013879:Thioredoxins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2; C023717:acacetin