Chronic hypoxia (CH) associated with obstructive pulmonary disease and sleep apnea often results in generalized pulmonary arterial constriction and vascular remodeling, subsequent pulmonary hypertension and right heart failure. Pulmonary arterial smooth muscle cell (PASMC) intracellular calcium ([Ca2+]i) plays a vital role in establishing pulmonary vascular resistance and it has become increasingly evident that increased Ca2+ influx contributes to both the vasoconstrictor and vascular remodeling responses in CH-induced pulmonary hypertension. Our laboratory has found a novel role for acid sensing ion channel 1 (ASIC1) in mediating store-operated Ca2+ entry (SOCE) in PASMC following CH. However, little is known about the mechanism(s) that govern ASIC1 trafficking, stability, and activation in PASMC. In addition, it is unclear how CH alters these mechanism(s) to increase functional ASIC1 at the plasma membrane. The overall objective of this application is to establish an important role for ASIC1 in the development of CH-induced pulmonary hypertension and potential mechanisms involved in this response. We will test the central hypothesis that ASIC1, through a novel mechanism of SOCE in PASMC, contributes to CH-induced increases in vascular reactivity and pulmonary hypertension with the following specific aims: 1) Determine the contribution of ASIC1 to CH-induced pulmonary hypertension. We will test the hypothesis that ASIC1 contributes to the active vasoconstrictor component of CH-induced pulmonary hypertension by assessing in vivo measurements of pulmonary arterial pressure, arterial remodeling, and vasoreactivity. 2) Identify the mechanism(s) responsible for ASIC1 membrane trafficking and how this is altered by CH. We will test the hypothesis that CH promotes PICK1 (protein interacting with C- kinase 1)-dependent ASIC1 trafficking to the membrane through increased RhoA-mediated actin polymerization by use of cell surface biotinylation assays, [Ca2+]i imaging, and live-cell confocal imaging of a fluorescently- labeled ASIC1 protein. 3) Examine the effect of cellular redox potential on ASIC1 activation. We hypothesize that decreased hydrogen peroxide (H2O2) following CH increases ASIC1 surface expression and channel activity. We will assess vasoreactivity and conduct [Ca2+]i imaging and electrophysiology studies to examine the role of reducing/oxidizing agents and H2O2 on ASIC1 channel activity and trafficking in PASMC. The proposed research is innovative through its focus on the previously undefined mechanisms of ASIC1 membrane trafficking, channel regulation and Ca2+ influx in the normal pulmonary circulation. In addition, our work is at the forefront of determining how hypoxia affects ASIC1 function in the hypertensive circulation. Successful completion of the proposed research will provide a mechanistic-based understanding of how ASIC1 contributes to CH- induced pulmonary hypertension and will significantly advance our knowledge of the cellular mechanisms responsible for altered PASMC Ca2+ homeostasis and vasoconstriction in the hypertensive pulmonary circulation. Ultimately, such knowledge has the potential to provide new directions in pulmonary hypertension therapy.

Public Health Relevance

According to the Federal Centers for Disease Control and Prevention (CDC), Chronic Lower Respiratory Diseases (CLRD) have surpassed stroke as the third leading cause of death in the United States. The goal of the proposed research is to determine novel mechanisms responsible for the development of hypoxic pulmonary hypertension (World Health Organization [WHO];group III). These studies are expected to lead to new therapeutic strategies to treat pulmonary hypertension and CLRD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Xiao, Lei
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University of New Mexico Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Herbert, Lindsay M; Resta, Thomas C; Jernigan, Nikki L (2018) RhoA increases ASIC1a plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia. Am J Physiol Cell Physiol 314:C166-C176
Zhang, Bojun; Naik, Jay S; Jernigan, Nikki L et al. (2018) Reduced membrane cholesterol after chronic hypoxia limits Orai1-mediated pulmonary endothelial Ca2+ entry. Am J Physiol Heart Circ Physiol 314:H359-H369
Jernigan, Nikki L; Naik, Jay S; Weise-Cross, Laura et al. (2017) Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension. PLoS One 12:e0180455
Zhang, Bojun; Naik, Jay S; Jernigan, Nikki L et al. (2017) Reduced membrane cholesterol limits pulmonary endothelial Ca2+ entry after chronic hypoxia. Am J Physiol Heart Circ Physiol 312:H1176-H1184
Gonzalez Bosc, Laura V; Plomaritas, Danielle R; Herbert, Lindsay M et al. (2016) ASIC1-mediated calcium entry stimulates NFATc3 nuclear translocation via PICK1 coupling in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 311:L48-58
Herbert, Lindsay M; Nitta, Carlos H; Yellowhair, Tracylyn R et al. (2016) PICK1/calcineurin suppress ASIC1-mediated Ca2+ entry in rat pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 310:C390-400
Jernigan, Nikki L (2015) Smooth muscle acid-sensing ion channel 1: pathophysiological implication in hypoxic pulmonary hypertension. Exp Physiol 100:111-20
Jernigan, Nikki L; Resta, Thomas C (2014) Calcium homeostasis and sensitization in pulmonary arterial smooth muscle. Microcirculation 21:259-71
Plomaritas, Danielle R; Herbert, Lindsay M; Yellowhair, Tracylyn R et al. (2014) Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 307:L419-30
Nitta, Carlos H; Osmond, David A; Herbert, Lindsay M et al. (2014) Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 306:H41-52

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