An abnormal TRPV4-related cytosolic Ca 2+ rise in response to uniaxial stretch in induced pluripotent stem cells-derived cardiomyocytes from dilated cardiomyopathy patients

摘要

Abstract 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 2+ ] i rise in hiPSC-CMs. Compared to control-hiPSC-CMs, DCM-hiPSC-CMs displayed a greater magnitude of [Ca 2+ ] i responses to the cell stretch of 10–15% elongation in length. This stretch-induced [Ca 2+ ] i rise was abolished by removal of extracellular Ca 2+ and markedly attenuated by TRPV4 inhibitors HC-067047 and RN-1734. Application of nifedipine and tranilast also reduced the [Ca 2+ ] i response but to a lesser degree. Moreover, the augmented [Ca 2+ ] i was decreased by cytochalasin D treatment. Taken together, our study for the first time demonstrated an abnormal TRPV4-related mechanosensitive Ca 2+ signaling in DCM-hiPSC-CMs. Highlights ? Patient specific DCM-hiPSC-CMs show a greater [Ca 2+ ] i response to uniaxial cell stretch. ? TRPV4 channels are the major contributor for this abnormal [Ca 2+ ] i response. ? L-type Ca 2+ channels and TRPV2 channels also partly contribute to this [Ca 2+ ] i response. ? Actin cytoskeleton is involved in the abnormal [Ca 2+ ] i response in DCM-hiPSC-CMs. ? TRPV4 and, to a lesser degree, TRPV2 and L-type Ca 2+ channels contribute to the abnormal [Ca 2+ ] i response in DCM-hiPSC-CMs.