Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules.

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.

Acacetin ameliorates cardiac hypertrophy by activating Sirt1/AMPK/PGC-1α pathway.

Cardiac hypertrophy is a major risk factor for developing heart failure. This study investigates the effects of the natural flavone acacetin on myocardial hypertrophy in cellular level and whole animals. In cardiomyocytes from neonatal rat with hypertrophy induced by angiotensin II (Ang II), acacetin at 0.3, 1, and 3 µM reduced the increased myocyte surface area, brain natriuretic peptide (BNP), and ROS production by upregulating anti-oxidative molecules (i.e. Nrf2, SOD1, SOD2, HO-1), anti-apoptotic protein Bcl-2, and downregulating the pro-apoptotic protein Bax and the inflammatory cytokine IL-6 in a concentration-dependent manner. In addition, acacetin rescued Ang II-induced impairment of PGC-1α, PPARα and pAMPK. These beneficial effects of acacetin were mediated by activation of Sirt1, which was confirmed in cardiac hypertrophy induced by abdominal aorta constriction (AAC) in SD rats. Acacetin prodrug (10 mg/kg, s.c., b.i.d.) treatment reduced the elevated artery blood pressure, improved the increased heart size and thickness of left ventricular wall and the ventricular fibrosis associated with inhibiting myocardial fibrosis and BNP, and reversed the impaired protective signal molecules including PGC-1α, Nrf2, PPARα, pAMPK and Sirt1 of left ventricular tissue. Our results demonstrate the novel pharmacological effect that acacetin ameliorates cardiac hypertrophy via Sirt1-mediated activation of AMPK/PGC-1α signal molecules followed by reducing oxidation, inflammation and apoptosis.

The Natural Flavone Acacetin Confers Cardiomyocyte Protection Against Hypoxia/Reoxygenation Injury via AMPK-Mediated Activation of Nrf2 Signaling Pathway.

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 µM) significantly decreased the apoptosis and reactive oxygen species 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.