Abstract Background : Oxidative stress has a considerable influence on endothelial cell dysfunction and atherosclerosis. Acacetin, an anti-inflammatory and antiarrhythmic, is frequently used in the treatment of myocarditis, albeit its role in managing atherosclerosis is currently unclear. Thus, we evaluated the regulatory effects of acacetin in maintaining endothelial cell function and further investigated whether the flavonoid could attenuate atherosclerosis in apolipoprotein E deficiency (apoE -/- ) mice. Methods : Different concentrations of acacetin were tested on EA.hy926 cells, either induced or non-induced by human oxidized low density lipoprotein (oxLDL), to clarify its influence on cell viability, cellular reactive oxidative stress (ROS) level, apoptotic ratios and other regulatory effects. In vivo, apoE -/- mice were fed either a western diet or a chow diet. Acacetin prodrug (15mg/kg) was injected subcutaneously two times a day for 12weeks. The effects of acacetin on the atherosclerotic process, plasma inflammatory factors and lipid metabolism were also investigated. Results : Acacetin significantly increased EA.hy926 cell viability by reducing the ratios of apoptotic and necrotic cells at 3μM. Moreover, 3μM Acacetin clearly decreased ROS levels and enhanced reductase protein expression through MsrA and Nrf2 pathway through phosphorylation of Nrf2 and degradation of Keap1. In vivo , acacetin treatment remarkably attenuated atherosclerosis by increasing reductase levels in circulation and aortic roots, decreasing plasma inflammatory factor levels as well as accelerating lipid metabolism in Western diet-fed apoE -/- mice. Conclusions : Our findings demonstrate the anti-oxidative and anti-atherosclerotic effects of acacetin, in turn suggesting its potential therapeutic value in atherosclerotic-related cardiovascular diseases (CVD).
Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO-1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3-3 μM) in a concentration-dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO-1 and SOD1/SOD2) and anti-apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.
Abstract Oxidative stress has a considerable influence on endothelial cell dysfunction and atherosclerosis. Acacetin, an anti‐inflammatory and antiarrhythmic, is frequently used in the treatment of myocarditis, albeit its role in managing atherosclerosis is currently unclear. Thus, we evaluated the regulatory effects of acacetin in maintaining endothelial cell function and further investigated whether the flavonoid could attenuate atherosclerosis in apolipoprotein E deficiency (apoE −/− ) mice. Different concentrations of acacetin were tested on EA.hy926 cells, either induced or non‐induced by human oxidized low‐density lipoprotein (oxLDL), to clarify its influence on cell viability, cellular reactive oxidative stress (ROS) level, apoptotic ratios and other regulatory effects. In vivo, apoE −/− mice were fed either a Western diet or a chow diet. Acacetin pro‐drug (15 mg/kg) was injected subcutaneously two times a day for 12 weeks. The effects of acacetin on the atherosclerotic process, plasma inflammatory factors and lipid metabolism were also investigated. Acacetin significantly increased EA.hy926 cell viability by reducing the ratios of apoptotic and necrotic cells at 3 μmol/L. Moreover, 3 μmol/L acacetin clearly decreased ROS levels and enhanced reductase protein expression through MsrA and Nrf2 pathway through phosphorylation of Nrf2 and degradation of Keap1. In vivo, acacetin treatment remarkably attenuated atherosclerosis by increasing reductase levels in circulation and aortic roots, decreasing plasma inflammatory factor levels as well as accelerating lipid metabolism in Western diet‐fed apoE −/− mice. Our findings demonstrate the anti‐oxidative and anti‐atherosclerotic effects of acacetin, in turn suggesting its potential therapeutic value in atherosclerotic‐related cardiovascular diseases (CVD).
Introduction: Ischemic cardiomyopathy induced by ischemia/reperfusion injury is a major cause of morbidity and mortality around the world; therefore it is important to seek the new strategy that can reduce myocardial ischemia/reperfusion injury. Our recent study reported that the natural flavone acacetin effectively protected myocardium against ischemia/reperfusion injury; however, the detailed mechanism was poorly understood. The present study investigates the potential molecular mechanism of acacetin in myocardioprotection against ischemia/reperfusion injury. Methods: An in vitro hypoxia/reoxygenation (H/R) model was established in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts, and potential molecular targets of acacetin in cardioprotection against H/R injury were determined in multiple biochemical and molecular biological approaches. Results: It was found that acacetin (0.3-3 μM) significantly decreased the apoptosis and ROS production induced by H/R injury in both cardiomyocyte...
The present study investigates the potential signal pathway of acacetin in cardioprotection against ischemia/reperfusion injury using an in vitro hypoxia/reoxygenation model in primary cultured neonatal rat cardiomyocytes and H9C2 cardiomyoblasts. It was found that acacetin (0.3-3 uM) significantly decreased the apoptosis and ROS production induced by hypoxia/reoxygenation injury in cardiomyocytes and H9C2 cardiomyoblasts via reducing the pro-apoptotic proteins Bax and cleaved-caspase-3 and increasing the anti-apoptotic protein Bcl-2. In addition, acacetin not only suppressed the release of pro-inflammatory cytokines TLR-4 and IL-6 induced by hypoxia/reoxygenation injury, but also increased the secretion of anti-inflammatory cytokine IL-10. Moreover, acacetin increased Nrf2 and HO-1 in a concentration-dependent manner, and rescued SOD1 and SOD2 reduction induced by hypoxia/reoxygenation insult. These beneficial effects of acacetin disappeared in cells with silenced Nrf2, suggesting that Nrf2 activation participates in the cardioprotective effect of acacetin against hypoxia/reoxygenation insult. However, acacetin-induced Nrf2 activation was not observed in cells with silenced AMPK and in ventricular tissues of rat hearts treated with the AMPK inhibitor Compound C and subjected to ischemia/reperfusion injury. Our results demonstrate for the first time that AMPK-mediated Nrf2 activation is involved in the cardiomyocytes protection of acacetin against hypoxia/reoxygenation injury by activating a series of intracellular signals involved in anti-oxidation, anti-inflammation, and anti-apoptosis.
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