Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease. Pulmonary vascular remodeling and vasoconstriction are the major causes for the elevated pulmonary vascular resistance in IPAH patients. Pulmonary vascular remodeling is characterized by significant medial and intimal hypertrophy, due partially to increased pulmonary arterial smooth muscle cell (PASMC) proliferation. Ca2+ signaling is one of the important signaling cascades that regulate cell proliferation and contraction. A rise in cytosolic Ca2+ ([Ca2+]cyt) in PASMC is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation. Enhanced Ca2+ entry as a result of upregulated membrane receptors and Ca2+ channels in PASMC may contribute to the development of pulmonary vascular remodeling and vasoconstriction in pulmonary hypertension (PH). Ca2+-sensing receptor (CaSR) is a G protein-coupled receptor that can be activated by extracellular Ca2+. Activation of CaSR increases synthesis of inositol 1,4,5 trisphosphate (IP3) and diacyglycerol (DAG). IP3 binds to IP3 receptor (IP3R) on the sarcoplasmic reticulum (SR) membrane and causes Ca2+ release. Depletion of Ca2+ from the SR induces store-operated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOC). DAG induces receptor-operated Ca2+ entry (ROCE) by activating receptor-operated Ca2+ channels (ROC). Ca2+-induced CaSR activation may also activate other signal transduction pathways to induce cell proliferation. We recently observed that a) Ca2+-induced increase in [Ca2+]cyt by activation of CaSR was enhanced, while mRNA and protein expression of CaSR was upregulated in IPAH-PASMC compared to normal PASMC; b) inhibition of CaSR in IPAH-PASMC with siRNA attenuated Ca2+-induced increase in [Ca2+]cyt and inhibited IPAH-PASMC proliferation; c) Ca2+-induced increase in [Ca2+]cyt by activation of CaSR was enhanced, while mRNA and protein expression of CaSR was upregulated in PASMC isolated from rats with monocrotaline (MCT)-induced PH compared to PASMC from normal rats; and d) blockade of CaSR with a calcilytic significantly inhibited the development of PH in rats injected with MCT. Based on these date, we hypothesize that Ca2+ is an extracellular ligand and an intracellular signaling element to induce pulmonary vasoconstriction and vascular remodeling; upregulation of CaSR contributes to the enhanced Ca2+ influx and augmented PASMC proliferation in IPAH while inhibition of CaSR is potentially a novel and effective therapeutic approach for PH.
Four Specific Aims are proposed to test the hypotheses: 1) to define the molecular mechanisms responsible for the upregulation of CaSR in PASMC from patients with IPAH and animals with experimental PH; 2) to define the downstream signaling cascades upon Ca2+-mediated activation of CaSR that lead to PASMC proliferation; 3) to define the molecular components of ROC and SOC that are functionally activated by Ca2+-mediated activation of CaSR; and 4) to examine whether knockdown of CaSR and/or blockade of CaSR by calcilytics prevents and/or reverses experimental PH in rats and mice.

Public Health Relevance

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and fatal disease that predominantly affects young women. Abnormalities in pulmonary arteries, the blood vessels in the lungs, have been shown to relate to the elevated blood pressure in the lungs. This study is designed to determine the role of a specific membrane receptor, calcium-sensing receptor, in the cellular processes that lead to the high blood pressure in the lungs of patients with this devastating disease, and to reveal potential novel targets for therapeutic approaches to treat IPAH.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1)
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Xiao, Lei
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University of Arizona
Internal Medicine/Medicine
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Chen, Jiwang; Sysol, Justin R; Singla, Sunit et al. (2017) Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 135:1532-1546
Tang, Haiyang; Desai, Ankit A; Yuan, Jason X-J (2016) Genetic Insights into Pulmonary Arterial Hypertension. Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms. Am J Respir Crit Care Med 194:393-7
Song, Shanshan; Ayon, Ramon J; Yuan, Jason X-J (2016) Ryanodine receptor-2: a necessity for gating store-operated Ca2+ channels. Cardiovasc Res 111:13-5
Tang, Haiyang; Yamamura, Aya; Yamamura, Hisao et al. (2016) Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 310:L846-59
Song, Shanshan; Jacobson, Krista N; McDermott, Kimberly M et al. (2016) ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. Am J Physiol Cell Physiol 310:C99-114
Fernandez, Ruby A; Wan, Jun; Song, Shanshan et al. (2015) Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J Physiol Cell Physiol 308:C581-93
Tang, Haiyang; Ayon, Ramon J; Yuan, Jason X-J (2015) New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S axis. EMBO Mol Med 7:689-91
Smith, Kimberly A; Voiriot, Guillaume; Tang, Haiyang et al. (2015) Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension. Am J Respir Cell Mol Biol 53:355-67
Tang, Haiyang; Fernandez, Ruby A; Yuan, Jason X-J (2015) miRNA208/Mef2 and TNF-? in right ventricular dysfunction: the transition from hypertrophy to failure. Circ Res 116:6-8
Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R et al. (2015) Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L208-20

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