An abnormal TRPV4-related cytosolic Ca2+ rise in response to uniaxial stretch in induced pluripotent stem cells-derived cardiomyocytes from dilated cardiomyopathy patients

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1863; no. 11; pp. 2964 - 2972
• Main Authors: Lu, Jun, Lee, Yee-Ki, Ran, Xinru, Lai, Wing-Hon, Li, Ronald A., Keung, Wendy, Tse, Kennis, Tse, Hung-Fat, Yao, Xiaoqiang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2017
• Subjects: Calcium signaling; Cell stretch; Dilated cardiomyopathy; Human induced pluripotent stem cells; Medicin och hälsovetenskap; TRPV4 channel; Calcium signaling; Human induced pluripotent stem cells; Cell stretch; TRPV4 channel; Dilated cardiomyopathy
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.07.021

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 [Ca2+]i rise in hiPSC-CMs. Compared to control-hiPSC-CMs, DCM-hiPSC-CMs displayed a greater magnitude of [Ca2+]i responses to the cell stretch of 10–15% elongation in length. This stretch-induced [Ca2+]i rise was abolished by removal of extracellular Ca2+ and markedly attenuated by TRPV4 inhibitors HC-067047 and RN-1734. Application of nifedipine and tranilast also reduced the [Ca2+]i response but to a lesser degree. Moreover, the augmented [Ca2+]i was decreased by cytochalasin D treatment. Taken together, our study for the first time demonstrated an abnormal TRPV4-related mechanosensitive Ca2+ signaling in DCM-hiPSC-CMs. •Patient specific DCM-hiPSC-CMs show a greater [Ca2+]i response to uniaxial cell stretch.•TRPV4 channels are the major contributor for this abnormal [Ca2+]i response.•L-type Ca2+ channels and TRPV2 channels also partly contribute to this [Ca2+]i response.•Actin cytoskeleton is involved in the abnormal [Ca2+]i response in DCM-hiPSC-CMs.•TRPV4 and, to a lesser degree, TRPV2 and L-type Ca2+ channels contribute to the abnormal [Ca2+]i response in DCM-hiPSC-CMs.