Li Bin, Xiong Weiyao, Liang Wen-Miin, Chiou Jian-Shiun, Lin Ying-Ju, Chang Alex C Y
Department of Cardiology and Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Health Services Administration, China Medical University, Taichung, Taiwan.
Front Cell Dev Biol. 2021 Apr 1;9:659177. doi: 10.3389/fcell.2021.659177. eCollection 2021.
Duchenne muscular dystrophy (DMD) related cardiomyopathy is the leading cause of early mortality in DMD patients. There is an urgent need to gain a better understanding of the disease molecular pathogenesis and develop effective therapies to prevent the onset of heart failure. In the present study, we used DMD human induced pluripotent stem cells (DMD-hiPSCs) derived cardiomyocytes (CMs) as a platform to explore the active compounds in commonly used Chinese herbal medicine (CHM) herbs. Single CHM herb (DaH, ZK, and CQZ) reduced cell beating rate, decreased cellular ROS accumulation, and improved structure of DMD hiPSC-CMs. Cross-comparison of transcriptomic profiling data and active compound library identified nine active chemicals targeting ROS neutralizing Catalase (CAT) and structural protein vascular cell adhesion molecule 1 (VCAM1). Treatment with Quecetin, Kaempferol, and Vitamin C, targeting CAT, conferred ROS protection and improved contraction; treatment with Hesperidin and Allicin, targeting VCAM1, induced structure enhancement via induction of focal adhesion. Lastly, overexpression of CAT or VCAM1 in DMD hiPSC-CMs reconstituted efficacious effects and conferred increase in cardiomyocyte function. Together, our results provide a new insight in treating DMD cardiomyopathy via targeting of CAT and VCAM1, and serves as an example of translating Bed to Bench back to Bed using a muti-omics approach.
杜氏肌营养不良症（DMD）相关的心肌病是DMD患者早期死亡的主要原因。迫切需要更好地了解该疾病的分子发病机制，并开发有效的治疗方法来预防心力衰竭的发生。在本研究中，我们使用源自DMD人诱导多能干细胞（DMD-hiPSCs）的心肌细胞（CMs）作为平台，以探索常用中药（CHM）中的活性化合物。单一的中药（大黄、枳壳和川芎嗪）降低了细胞搏动率，减少了细胞内活性氧的积累，并改善了DMD hiPSC-CMs的结构。转录组分析数据与活性化合物库的交叉比较确定了九种靶向活性氧中和酶过氧化氢酶（CAT）和结构蛋白血管细胞粘附分子1（VCAM1）的活性化学物质。靶向CAT的槲皮素、山奈酚和维生素C治疗可提供活性氧保护并改善收缩功能；靶向VCAM1的橙皮苷和大蒜素治疗通过诱导粘着斑来增强结构。最后，在DMD hiPSC-CMs中过表达CAT或VCAM1可恢复有效作用并提高心肌细胞功能。总之，我们的研究结果为通过靶向CAT和VCAM1治疗DMD心肌病提供了新的见解，并作为使用多组学方法将临床转化为实验再回到临床的一个例子。
