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The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia\/reperfusion injury in an<jats:italic>in vivo<\/jats:italic>rat model. We found that intravenous administration of acacetin prodrug (10\u2009mg\/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<jats:italic>ex vivo<\/jats:italic>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 TNF\u03b1, and decreased myocyte apoptosis induced by ischemia\/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant<jats:italic>in vivo<\/jats:italic>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.<\/jats:p>","DOI":"10.1038\/srep36435","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T11:22:07Z","timestamp":1478517727000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Water-soluble acacetin prodrug confers significant cardioprotection against ischemia\/reperfusion injury"],"prefix":"10.1038","volume":"6","author":[{"given":"Hui","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Jun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kui-Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Ying","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Sheng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Rong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,7]]},"reference":[{"key":"BFsrep36435_CR1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/clpt.2011.173","volume":"90","author":"JC Kovacic","year":"2011","unstructured":"Kovacic, J. 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