Acid-Sensitive Ion Channels Are Expressed in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are potential sources for cardiac regeneration and drug development. hiPSC-CMs express all the cardiac ion channels and the unique cardiac Ca 2+ -signaling phenotype. In this study, we tested for expression of acid sensing ion channels (ASICs) in spontaneously beating cardiomyocytes derived from three different hiPSC lines (IMR-90, iPSC-K3, and Ukki011-A). Rapid application of solutions buffered at pH 6.7, 6.0, or 5.0 triggered rapidly activating and slowly inactivating voltage-independent inward current that reversed at voltages positive to E Na , was suppressed by 5 mM amiloride and withdrawal of [Na + ] o , like neuronal ASIC currents. ASIC currents were expressed at much lower percentages and densities in undifferentiated hiPSC and in dermal fibroblasts. ASIC1 mRNA and protein were measured in first 60 days but decreased in 100 days postdifferentiation hiPSC cultures. Hyperacidification (pH 5 and 6) also triggered large Ca 2+ transients in intact hiPSC-CMs that were neither ruthenium red nor amiloride-sensitive, but were absent in whole cell-clamped hiPSC-CMs. Neither ASIC1 current nor its protein was detected in rat adult cardiomyocytes, but hyperacidification did activate smaller and slowly activating currents with drug sensitivity similar to TRPV channels. Considering ASIC expression in developing but not adult myocardium, a role in heart development is likely.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury

“…Although ASICs, and in particular ASIC1a, are generally associated with the central and peripheral nervous systems, 58 our expression analyses revealed that ASIC1 is present in both rodent and human cardiomyocytes and is not differentially regulated at the transcriptional level as a result of cellular ischemia in vitro or in vivo. 35 Our evidence of ASIC1 expression in the heart is supported by recent studies that identified ASIC-like currents in hiPSC-CMs 59 and rat cardiomyocytes. 24 In neurons, ASIC1a activation leads to cell death through several possible mechanisms, including calcium overload, 60 regulation of mitochondrial permeability transition pores, 61 and the initiation of necroptosis through direct interaction with, and activation of, RIPK1 (receptor-interacting protein kinase 1).…”

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

“…Although ASICs, and in particular ASIC1a, are generally associated with the central and peripheral nervous systems 53 , our expression analyses revealed that ASIC1 is present in both rodent and human cardiomyocytes, and is not differentially regulated at the transcriptional level as a result of cellular ischemia in vitro or in vivo 33 . Our evidence of ASIC1a expression in the heart is supported by recent studies that identified ASIC-like currents in hiPSC-CMs 54 and rat cardiomyocytes 23 . In neurons, there are several possible mechanisms by which ASIC1a activation leads to cell death including calcium overload 55 , regulation of mitochondrial permeability transition (MPT) pores 56 , and the initiation of necroptosis through direct interaction with, and activation of, RIPK1 45 .…”

The role of acid sensing ion channels in the cardiovascular function

“…In addition, ASIC-like currents were also observed in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), derived from three different hiPSC lines (IMR-90, iPSC-K3, and Ukki011-A). However, in this same study, ASIC-like currents and their protein subunits were absent in adult rat cardiomyocytes ( Zhang et al, 2019 ). This evidence indicates the functional expression of ASIC channels in both, the developing and adult mammalian myocardium.…”