Data_Sheet_1_Targeting of CAT and VCAM1 as Novel Therapeutic Targets for DMD Cardiomyopathy.PDF

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）相关心肌病是DMD患者早期死亡的主要原因。迫切需要深入理解疾病的分子发病机制，并开发有效的治疗策略以预防心力衰竭的发生。在本研究中，我们利用源自DMD人类诱导多能干细胞（DMD-hiPSCs）的心肌细胞（CMs）作为平台，探索常用中药（CHM）中的活性成分。单味中药（如DaH、ZK和CQZ）可降低细胞搏动速率，减少细胞内活性氧（ROS）的积累，并改善DMD hiPSC-CMs的结构。通过转录组学分析数据和活性成分库的交叉比较，鉴定出九种针对ROS中和的过氧化氢酶（CAT）和结构蛋白血管细胞粘附分子1（VCAM1）的活性化合物。针对CAT的奎克汀、槲皮素和维生素C治疗提供了ROS保护并改善了收缩功能；针对VCAM1的橙皮苷和蒜素治疗通过诱导焦点粘附诱导结构增强。最后，在DMD hiPSC-CMs中过表达CAT或VCAM1可恢复有效的治疗效果，并赋予心肌细胞功能的提升。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，并作为利用多组学方法将床边研究转化为临床应用的一个范例。