Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension

Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential (E-m) of pulmonary arterial smooth muscle cells (PASMCs). It is well-known that the underlying mechanism of this depolarization includes inhibition of K+ channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid-sensing ion channel 1 (ASIC1), a non-selective cation channel (NSCC) that conducts both Na+ and Ca2+, is present in PASMCs and contributes to the development of chronic hypoxia (CH)-induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1-mediated Na+ influx contributes to PASMC E-m regulation following CH-induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure-induced depolarization. In addition to a decrease in PASMC whole-cell K+ currents following CH, we demonstrate that whole-cell NSCC currents are increased and essential to the persistent CH-induced E-m depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout ofASIC1 (Asic1(-/-)) preventsCH-inducedEm depolarization and largely inhibitswhole-cell NSCC currents, without affecting whole-cell K+ currents. Our results show a combination of factors, including inhibition of K+ efflux and augmented Na+ influx, mediate CH-induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of E-m in PASMCs during CH-induced pulmonary hypertension.

Automated summary

Pulmonary hypertension is characterized by sustained vasoconstriction and remodeling of the small pulmonary arteries. Acid-sensing ion channel 1 (ASIC1) plays a role in chronic hypoxia-induced pulmonary hypertension and contributes to the depolarization of pulmonary arterial smooth muscle cells. Na+ influx, mediated by ASIC1, is essential for the persistent depolarization in PASMCs during chronic hypoxia.