Abstract
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.
Highlights
With blank rat plasma. (C) high-performance liquid chromatography (HPLC) with rat plasma at 5 min after intravenous administration of acacetin prodrug (250 μg/kg/min). (D) HPLC with rat plasma at 40 min after intravenous administration of acacetin prodrug
Our results demonstrated that intravenous administration of acacetin prodrug was very effective in reducing ventricular arrhythmias and myocardial infarct size induced by ischemia/reperfusion injury in anesthetized rats
Acacetin was not detected in rat blood plasma before administration of acacetin prodrug (Fig. 1B), and significant plasma level of acacetin was observed at 5 min (Fig. 1C) and 40 min (Fig. 1D) with acacetin prodrug administration
Summary
With blank rat plasma (before administration of acacetin prodrug). (C) HPLC with rat plasma at 5 min after intravenous administration of acacetin prodrug (250 μg/kg/min). (D) HPLC with rat plasma at 40 min after intravenous administration of acacetin prodrug. With blank rat plasma (before administration of acacetin prodrug). We investigate whether this water-soluble acacetin prodrug is cardioprotective against ischemia/reperfusion injury. Our results demonstrated that intravenous administration of acacetin prodrug was very effective in reducing ventricular arrhythmias and myocardial infarct size induced by ischemia/reperfusion injury in anesthetized rats. Molecular mechanism analysis in ex vivo rat hearts revealed that acacetin prevented ischemia/reperfusion reduction of mitochondrial anti-oxidative kinases SOD-2 and thioredoxin as well as reduced inflammatory cytokines TLR4, IL-6 and TNFα, thereby inhibited myocyte apoptosis induced by ischemia/reperfusion
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