Abstract：
Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization.
摘要：
心力衰竭是一种危及生命的心血管疾病，以心脏肥大为特征，炎症和纤维化。中药复方强心饮(QXY)治疗心力衰竭有效,但其作用机制尚不明确。本研究旨在鉴定QXY的活性成分并探讨其对心肌肥厚的保护作用机制。我们发现QXY可以显着抵抗异丙肾上腺素（ISO）诱导的斑马鱼心脏肥大和功能障碍。八个化合物,包括苯甲酰基美松碱（BMA），白曲内酯I(ATLI)，淫羊藿苷(ICA),槲皮苷（QUE），补骨脂素(PRN),山奈酚（KMP），从QXY中鉴定出阿魏酸（FA）和原儿茶酸（PCA）。PRN,KMP和淫羊藿苷(ICT)，ICA的活性药物成分，预防ISO诱导的斑马鱼心肌肥厚和功能障碍。在用ISO处理的H9c2心肌细胞中，QXY显著阻断了钙的流入，减少细胞内脂质过氧化产物MDA，刺激ATP产生和增加线粒体膜电位。QXY还抑制ISO诱导的心肌细胞肥大和细胞骨架重组。机械上,QXY增强Smad家族成员2（SMAD2）和肌球蛋白磷酸酶靶亚基1（MYPT1）的磷酸化，并抑制肌球蛋白轻链（MLC）的磷酸化。总之,PRN,KMP和ICA是QXY的主要活性成分，主要通过阻断钙内流和抑制线粒体功能障碍以及细胞骨架重组来防止ISO诱导的心肌肥大和功能障碍。
