Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong Special Administrative Regions of China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong Special Administrative Regions of China.
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Phytomedicine. 2024 Jul 25;130:155717. doi: 10.1016/j.phymed.2024.155717. Epub 2024 May 9.
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.
心力衰竭是一种危及生命的心血管疾病，其特征为心肌肥大、炎症和纤维化。中药芪苈强心（QXY）对心力衰竭的治疗有效，但具体机制尚不清楚。本研究旨在鉴定 QXY 的活性成分，并探讨其防治心肌肥大的作用机制。我们发现 QXY 能显著防治异丙肾上腺素（ISO）诱导的斑马鱼心肌肥大和功能障碍。从 QXY 中鉴定出包括苯甲酰次乌头原碱（BMA）、苍术苷 I（ATL I）、淫羊藿苷（ICA）、槲皮素（QUE）、补骨脂素（PRN）、山柰酚（KMP）、阿魏酸（FA）和原儿茶酸（PCA）在内的 8 种化合物。PRN、KMP 和 ICA 的活性成分 ICA 均能预防 ISO 诱导的斑马鱼心肌肥大和功能障碍。在 ISO 处理的 H9c2 心肌细胞中，QXY 显著阻断钙内流，减少细胞内脂质过氧化产物 MDA，刺激 ATP 产生，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排。机制上，QXY 增强了 Smad 家族成员 2（SMAD2）和肌球蛋白磷酸酶靶亚单位 1（MYPT1）的磷酸化，抑制肌球蛋白轻链（MLC）的磷酸化。综上所述，PRN、KMP 和 ICA 是 QXY 防治 ISO 诱导的心肌肥大和功能障碍的主要活性成分，其作用机制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排。
