Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, 361009, China.
Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, 361009, China; Nanjing Amazigh Pharma Limited, Nanjing, Jiangsu, 210032, China.
Eur J Pharmacol. 2022 Apr 5;920:174858. doi: 10.1016/j.ejphar.2022.174858. Epub 2022 Feb 24.
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.
心肌肥厚是心力衰竭发展的主要危险因素。本研究探讨了天然黄酮类化合物 Acacetin 在细胞水平和整体动物水平对心肌肥厚的影响。在血管紧张素 II（Ang II）诱导的新生大鼠心肌细胞肥大模型中，Acacetin 在 0.3、1 和 3 μM 浓度下，通过上调抗氧化分子（即 Nrf2、SOD1、SOD2、HO-1）、抗凋亡蛋白 Bcl-2 和下调促凋亡蛋白 Bax 和炎症细胞因子 IL-6，降低了心肌细胞表面积、脑钠肽（BNP）和 ROS 产生的增加，呈浓度依赖性。此外，Acacetin 挽救了 Ang II 诱导的 PGC-1α、PPARα 和 pAMPK 损伤。Acacetin 的这些有益作用是通过 Sirt1 的激活介导的，这在 SD 大鼠腹主动脉缩窄（AAC）诱导的心肌肥厚中得到了证实。Acacetin 前药（10 mg/kg，sc，bid）治疗降低了升高的动脉血压，改善了左心室壁厚度和心室纤维化的增加以及与抑制心肌纤维化和 BNP 相关的左心室组织中受损的保护信号分子，包括 PGC-1α、Nrf2、PPARα、pAMPK 和 Sirt1。我们的研究结果表明，Acacetin 通过 Sirt1 介导的 AMPK/PGC-1α 信号分子的激活来改善心肌肥厚，从而减少氧化、炎症和细胞凋亡，这是一种新的药理学作用。
