ASIC1-dependent Ca2+ influx is required for NFATc3 activation in chronic hypoxia-induced pulmonary hypertension (1090.12)

The development of chronic hypoxia (CH)-induced pulmonary hypertension is associated with 1) the activation of the Ca2+-dependent transcription factor, nuclear factor of activated T-cells isoform c3 (NFATc3), and 2) enhanced acid sensing ion channel 1 (ASIC1)-dependent Ca2+ influx in pulmonary arterial smooth muscle cells (PASMC). Therefore, we hypothesize that ASIC1-mediated Ca2+ influx increases NFATc3 nuclear translocation in pulmonary vascular smooth muscle. To test this hypothesis we first examined the effect of ASIC1 inhibition on NFATc3 nuclear translocation in PASMC in response to endothelin-1 (ET-1; 10-7 M). Inhibition of ASIC1 with psalmotoxin-1 (20 nM) diminished ET-1 induced Ca2+ influx and NFATc3 nuclear import. In addition, ET-1 mediated pulmonary arterial vasoconstriction and Ca2+ influx following CH (1 wk @ 380 mmHg) were blunted in ASIC1 knockout mice (ASIC1-/-) compared to the ASIC1 wildtype mice (ASIC1+/+). Similarly, CH increased pulmonary vascular smooth muscle NFATc3 nuclear transloc...