Pulmonary hypertension (pHTN) is a complex, progressive condition leading to increased pulmonary vascular resistance, right heart failure and ultimately death. Although pHTN arises from a variety of genetic and pathogenic causes, it is widely recognized that structural alterations in the vascular wall contribute to all forms of pHTN. A chronic shift in cellular metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis underlies the hyperproliferative and anti-apoptotic phenotype within the pulmonary vasculature. These metabolic derangements are accompanied by H+ extrusion creating an alkalotic intracellular pH while acidifying the extracellular microenvironment; conditions that activate the H+-gated acid sensing ion channel 1 (ASIC1). ASIC1 conducts both Na+ and Ca2+ and activation leads to membrane depolarization and variety of intracellular Ca2+ signaling events. Our previous studies show ASIC1 contributes to the development of pHTN and is associated with greater localization of ASIC1 at the plasma membrane of pulmonary arterial smooth muscle cells (PASMC) and loss of ASIC1 in the mitochondria. Neither the role of ASIC1 in the mitochondria, nor the contribution of ASIC1 to metabolic-mitochondrial dysfunction are known. Therefore, the overall objective of this application is to determine the contribution of ASIC1 to the metabolic derangements that promote a proliferative, apoptosis-resistant phenotype associated with pHTN. We will test the central hypothesis that ASIC1 contributes to metabolic dysfunction in pHTN as a result of altered subcellular localization and regulation of PASMC plasma membrane and mitochondrial membrane potential with the following two specific aims: 1) Determine the impact of altered cellular metabolism on ASIC1 localization and activation. We will test the working hypothesis that enhanced glucose uptake and subsequent acidification of the extracellular microenvironment in pHTN leads to increased localization/activation of ASIC1 at the plasma membrane, plasma membrane depolarization, and proliferation. 2) Examine the functional role of mitochondrial ASIC1 (mtASIC1) in regulation of mitochondrial membrane potential (??m) and apoptosis. We will test the working hypothesis that mtASIC1 contributes to mitochondrial ??m depolarization and apoptosis. Furthermore, loss of mtASIC1 in pHTN leads to mitochondrial ??m hyperpolarization and apoptosis-resistance. Successful completion of the proposed studies is expected to define a role for ASIC1 in regulating mitochondrial dynamics and metabolic dysfunction. These outcomes will enable a fundamental understanding of ASIC1 in various proliferative and degenerative diseases, which will permit future studies to evaluate the therapeutic potential of ASIC1.
The experiments in this proposal will examine the cellular mechanism involved in the development of pulmonary hypertension, a progressive and life-threatening disease with limited treatment options. In particular, we will determine the role of acid-sensing ion channel 1 (ASIC1) in mediating metabolic changes that leads to enhanced proliferation within the pulmonary vasculature during development of pulmonary hypertension. Such information is crucial to advancing treatment and developing new therapeutic options to treat this devastating disease.
|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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