Chronic hypoxia (CH) occurs in many cardiopulmonary diseases and high altitude residency. This common clinical stress causes the remodeling, vasoconstriction and hypertension in the pulmonary artery (PA). These cellular responses primarily result from an increase in intracellular Ca concentration ([Ca2+]i, i.e., Ca2+ signaling) in PA smooth muscle cells (PASMCs). However, the underlying molecular mechanisms are not fully understood, and current therapeutic options for pulmonary hypertension (PH) are limited. Based on our preliminary data and previous publications, we propose a very innovative central hypothesis that CH causes Rieske iron-sulfur protein (RISP)-mediated mitochondrial reactive oxygen species (ROS) production, disrupts FK506 binding protein 12.6 (FKBP12.6)/ryanodine receptor-2 (RyR2) complex, causes RyR2 hyperfunction, increases Ca2+ release, activates calcineurin, cytoplasmic nuclear factor of activated T- cells (NFATc) and nuclear factor-kB (NFkB), and increases cyclin expression in PASMCs, leading to PA remodeling, contraction and hypertension. To test this exciting hypothesis, we will employ complementary, state-of-the-art laser scanning confocal microscopy, patch clamp recording, gene-manipulation, double immunofluorescence staining, florescent resonance energy transfer, and other approaches to address the following fundamental questions (Specific Aims): (1) is the FKBP12.6/RyR2 complex disrupted as a result of RISP-mediated mitochondrial ROS production in PASMCs from mice following CH; (2) does the disruption of the FKBP12.6/RyR2 complex mediate CH-induced PA remodeling, contraction and hypertension; and (3) is the role of FKBP12.6/RyR2 complex disruption in CH-induced responses in PAs mediated by the calcineurin-dependent, NF-kB/NFATc-mediated cyclin signaling axis? We fully believe that the findings from the proposed studies will greatly improve our current knowledge of the cellular molecular mechanisms for PA remodeling, constriction and hypertension, and help to fully understand what and how Ca2+ downstream signaling axis is in hypoxic. It is expected that the results may also aid in the creation of novel, specific and more effective therapeutic targets for the treatment of PAH and other relevant pulmonary vascular diseases, with a great potential for revolutionizing clinical practices.

Public Health Relevance

Pulmonary hypertension is a progressive lung disease with a high mortality. This devastating disease often occurs as a result of cardiopulmonary diseases, high altitude residence, and even without any known cause. Currently, there is no cure for pulmonary artery hypertension, and the medications are limited, which may largely be due to an incomplete understanding of its pathogenesis. In this project, we propose to determine the potentially essential role of ryanodine receptor-2 (calcium release channel) and its associated inhibitory molecule FK506 binding protein 12.6 in the development of hypoxia-induced pulmonary artery hypertension as well as the underlying molecular mechanisms. The findings from the proposed studies will greatly advance our current knowledge about the molecular processes of pulmonary artery hypertension, and may also help to identify novel and more effective therapeutic targets for the treatment of this disease and other relevant lung disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122865-03
Application #
9186562
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2014-12-15
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
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Adam, Alejandro Pablo; Zheng, Yun-Min; Wang, Yong-Xiao (2018) The changes in endothelial cytoskeleton and calcium in vascular barrier breakdown: a response of ever-growing complexity. Pulm Circ 8:2045893218754854
Xiao, Jun-Hua; Hao, Qiong-Yu; Wang, Katie et al. (2017) Emerging Role of MicroRNAs and Long Noncoding RNAs in Healthy and Diseased Lung. Adv Exp Med Biol 967:343-359
Zhao, Qing-Yang; Peng, Yong-Bo; Luo, Xiao-Jing et al. (2017) Distinct Effects of Ca2+ Sparks on Cerebral Artery and Airway Smooth Muscle Cell Tone in Mice and Humans. Int J Biol Sci 13:1242-1253
Song, Tengyao; Zheng, Yun-Min; Wang, Yong-Xiao (2017) Cross Talk Between Mitochondrial Reactive Oxygen Species and Sarcoplasmic Reticulum Calcium in Pulmonary Arterial Smooth Muscle Cells. Adv Exp Med Biol 967:289-298
Di Mise, Annarita; Wang, Yong-Xiao; Zheng, Yun-Min (2017) Role of Transcription Factors in Pulmonary Artery Smooth Muscle Cells: An Important Link to Hypoxic Pulmonary Hypertension. Adv Exp Med Biol 967:13-32
Song, Tengyao; Zheng, Yun-Min; Vincent, Peter A et al. (2016) Canonical transient receptor potential 3 channels activate NF-?B to mediate allergic airway disease via PKC-?/I?B-? and calcineurin/I?B-? pathways. FASEB J 30:214-29
Parajuli, Shankar P; Zheng, Yun-Min; Levin, Robert et al. (2016) Big-conductance Ca(2+)-activated K(+) channels in physiological and pathophysiological urinary bladder smooth muscle cells. Channels (Austin) 10:355-364
Wei, Ming-Yu; Xue, Lu; Tan, Li et al. (2015) Involvement of large-conductance Ca2+-activated K+ channels in chloroquine-induced force alterations in pre-contracted airway smooth muscle. PLoS One 10:e0121566
Song, Tengyao; Hao, Qiongyu; Zheng, Yun-Min et al. (2015) Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309:L1455-66

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