The Journal of Nutritional Biochemistry ( IF 5.6 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.jnutbio.2019.108339 Levi W Evans 1 , Abigail Bender 2 , Leah Burnett 2 , Luis Godoy 3 , Yi Shen 4 , Dante Staten 5 , Tong Zhou 2 , Jeffrey E Angermann 5 , Bradley S Ferguson 6
Pathological cardiac hypertrophy is a classical hallmark of heart failure. At the molecular level, inhibition of histone deacetylase (HDAC) enzymes attenuate pathological cardiac hypertrophy in vitro and in vivo. Emodin is an anthraquinone that has been implicated in cardiac protection. However, it is not known if the cardio-protective actions for emodin are mediated through HDAC-dependent regulation of gene expression. Therefore, we hypothesized that emodin would attenuate pathological cardiac hypertrophy via inhibition of HDACs, and that these actions would be reflected in an emodin-rich food like rhubarb. In this study, we demonstrate that emodin and Turkish rhubarb containing emodin inhibit HDAC activity in vitro, with fast-on, slow-off kinetics. Moreover, we show that emodin increased histone acetylation in cardiomyocytes concomitant to global changes in gene expression; gene expression changes were similar to the well-established pan-HDAC inhibitor trichostatin A (TSA). We additionally present evidence that emodin inhibited phenylephrine (PE) and phorbol myristate acetate (PMA)-induced hypertrophy in neonatal rat ventricular myocytes (NRVMs). Lastly, we demonstrate that the cardioprotective actions of emodin are translated to an angiotensin II (Ang) mouse model of cardiac hypertrophy and fibrosis and are linked to HDAC inhibition. These data suggest that emodin blocked pathological cardiac hypertrophy, in part, by inhibiting HDAC-dependent gene expression changes.
中文翻译:
大黄素和富含大黄素的大黄抑制组蛋白脱乙酰基酶(HDAC)活性和心肌细胞肥大。
病理性心脏肥大是心力衰竭的经典标志。在分子水平上,组蛋白脱乙酰基酶(HDAC)酶的抑制作用可在体外和体内减弱病理性心脏肥大。大黄素是一种蒽醌,与心脏保护有关。但是,尚不清楚大黄素的心脏保护作用是否通过基因表达的HDAC依赖性调节来介导。因此,我们假设大黄素会通过抑制HDAC减轻病理性心脏肥大,并且这些作用将反映在大黄素含量较高的食物中,例如大黄。在这项研究中,我们证明大黄素和含有大黄素的土耳其大黄在体外抑制HDAC活性,具有快速开关的动力学。此外,我们表明大黄素增加了心肌细胞中组蛋白的乙酰化,并伴随着基因表达的整体变化。基因表达的变化与公认的泛HDAC抑制剂曲古抑菌素A(TSA)相似。我们还提供了大黄素抑制新生大鼠心室肌细胞(NRVMs)中去氧肾上腺素(PE)和佛波醇肉豆蔻酸乙酸酯(PMA)诱导的肥大的证据。最后,我们证明了大黄素的心脏保护作用被转化为心脏肥大和纤维化的血管紧张素II(Ang)小鼠模型,并与HDAC抑制有关。这些数据表明,大黄素部分通过抑制HDAC依赖性基因表达变化来阻止病理性心肌肥大。