School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong, Hong Kong, China; Guangzhou Institutes of Biomedicine and Health, China.
Biochim Biophys Acta Mol Basis Dis. 2017 Nov;1863(11):2964-2972. doi: 10.1016/j.bbadis.2017.07.021. Epub 2017 Jul 25.
Dilated cardiomyopathy (DCM) is cardiac disease characterized by increased left ventricular chamber volume and decreased systolic function. DCM patient-specific human induced-pluripotent stem cells-derived cardiomyocytes (DCM-hiPSC-CMs) were generated. We found that uniaxial stretch elicited a cytosolic [Ca] rise in hiPSC-CMs. Compared to control-hiPSC-CMs, DCM-hiPSC-CMs displayed a greater magnitude of [Ca] responses to the cell stretch of 10-15% elongation in length. This stretch-induced [Ca] rise was abolished by removal of extracellular Ca and markedly attenuated by TRPV4 inhibitors HC-067047 and RN-1734. Application of nifedipine and tranilast also reduced the [Ca] response but to a lesser degree. Moreover, the augmented [Ca] was decreased by cytochalasin D treatment. Taken together, our study for the first time demonstrated an abnormal TRPV4-related mechanosensitive Ca signaling in DCM-hiPSC-CMs.
扩张型心肌病（DCM）是一种以左心室腔容积增加和收缩功能降低为特征的心脏疾病。生成了扩张型心肌病患者特异性的人诱导多能干细胞衍生的心肌细胞（DCM-hiPSC-CMs）。我们发现，单轴拉伸在 hiPSC-CMs 中引起细胞溶质 [Ca]升高。与对照 hiPSC-CMs 相比，DCM-hiPSC-CMs 在长度延长 10-15%的细胞拉伸下表现出更大幅度的 [Ca]反应。这种拉伸诱导的 [Ca]升高被去除细胞外 Ca 所消除，并被 TRPV4 抑制剂 HC-067047 和 RN-1734 显著减弱。硝苯地平和曲尼司特的应用也降低了 [Ca]反应，但程度较小。此外，细胞松弛素 D 处理可减少 [Ca]的增加。总之，我们的研究首次证明了 DCM-hiPSC-CMs 中存在异常的 TRPV4 相关机械敏感 Ca 信号。
