Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction

作者：Jernigan Nikki L^*; Herbert Lindsay M; Walker Benjimen R; Resta Thomas C

来源：American Journal of Physiology - Cell Physiology, 2012, 302(6): C931-C940.

DOI：10.1152/ajpcell.00332.2011

• degenerin/epithelial Na+ channel
• capacitative calcium entry
• psalmotoxin-1
• pulmonary hypertension
• receptor-operated calcium entry
• L-type voltage-gated calcium entry

Jernigan NL, Herbert LM, Walker BR, Resta TC. Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction. Am J Physiol Cell Physiol 302: C931-C940, 2012. First published December 14, 2011; doi:10.1152/ajpcell.00332.2011.-Acidsensingion channel 1 (ASIC1) is a newly characterized contributor to store-operated Ca2+ entry (SOCE) in pulmonary vascular smooth muscle (VSM). Since SOCE is implicated in elevated basal VSM intracellular Ca2+ concentration ([Ca2+](i)) and augmented vasoconstriction in chronic hypoxia (CH)-induced pulmonary hypertension, we hypothesized that ASIC1 contributes to these responses. To test this hypothesis, we examined effects of the specific pharmacologic ASIC1a inhibitor, psalmotoxin 1 (PcTX1), on vasoconstrictor and vessel wall [Ca2+](i) responses to UTP and KCl (depolarizing stimulus) in fura-2-loaded, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) Wistar rats. PcTX1 had no effect on basal vessel wall [Ca2+](i), but attenuated vasoconstriction and increases in vessel wall [Ca2+](i) to UTP in arteries from control and CH rats; normalizing responses between groups. In contrast, responses to the depolarizing stimulus, KCl, were unaffected by CH exposure or PcTX1. Upon examining potential Ca2+ influx mechanisms, we found that PcTX1 prevented augmented SOCE following CH. Exposure to CH resulted in a significant increase in pulmonary arterial ASIC1 protein. This study supports a novel role of ASIC1 in elevated receptor-stimulated vasoconstriction following CH which is likely mediated through increased ASIC1 expression and SOCE.

• 出版日期2012-3