Chronic hypoxia (CH)-induced sustained increases in vascular tone and pulmonary vascular remodeling play key roles in the pathogenesis of chronic hypoxic pulmonary hypertension (CHPH). Despite progresses have been made on exploring the role of Ca2+ in these processes, the underlying molecular mechanisms, however, remain largely unknown. Bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-2 (TGF-2) superfamily, are known as critical regulators in mammalian development, cell proliferation, differentiation and apoptosis. Recently, the identification of germline mutation of BMP receptor II (BMPRII) in familial pulmonary hypertension and other associated group of evidence indicate the implication of abnormal BMP signaling in the pathogenesis of pulmonary hypertension. In particular, ug-regulation of bone morphogenetic protein 4 (BMP4) by CH was suggested to be an important factor that influences the development of CHPH. We previously demonstrated that CH elevated basal intracellular [Ca2+] ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) due in large part to enhanced store-operated calcium entry (SOCE) through store-operated Ca2+ channels (SOCCs) likely composed of canonical transient receptor potential proteins (TRPCs). In our recent studies, we obtained data showing a role of BMP4 in regulation of TRPCs expression and Ca2+ influx. These data include: 1) BMP4 treatment increased TRPC1 and TRPC6 expression, SOCE and basal [Ca2+]i in PASMCs;2) Exposure to CH increased mRNA and protein expression of TRPC1 and TRPC6, SOCE and basal [Ca2+]i in PASMCs, and these CH-induced increases were attenuated by knockdown of BMP4 expression via specific BMP4 siRNA, or BMP4 depletion using its antagonist noggin;2) CH enhanced both mRNA and protein expressions of BMP4 in mouse lung;3) Overexpression of HIF-1a increased BMP4 expression in PASMCs, and the CH-induced increases of BMP4 expression were impaired in HIF-1a partially deficient mice. These results suggest that BMP4 participate in the regulation of Ca2+ homeostasis in PASMCs during CH via modulation of TRPC channels, acting either in downstream of HIF-1a or in concert with HIF-1a dependent up-regulation of TRPCs. On the basis of the above findings and some other data in our studies, we hypothesize that the increased [Ca2+]i in PASMCs caused by CH is due to or partially due to HIF-1 dependent upregulation of BMP4, which leads to increases in TRPCs expression, SOCE and basal [Ca2+]i in distal PASMCs, thereby contributing to CHPH. To test this hypothesis, we will perform experiments in lung, PA and/or PASMCs using the combined techniques of microfluorescence measurements and molecular biology to accomplish the following specific aims: 1) Determine the roles of HIF-1 and BMP4 in up-regulation of TRPCs expression during CH;2) Determine BMP4 receptors and antagonist(s) that are responsible for hypoxic increases of TRPCs expression;3) Determine the signaling pathway through which BMP4 regulates TRPCs expression in PASMCs;4) Determine which TRPC contributes to the increases of SOCE and basal [Ca2+]i in response to CH.

Public Health Relevance

Pulmonary hypertension (PH) is a progressive devastating disease characterized by high blood pressure in the lungs;its mechanisms remain poorly understood. Hypoxia, an important trigger of PH, has been found to enhance calcium signaling in pulmonary artery smooth muscle cells, causing cell proliferation and constriction. Our study focuses on investigation of whether and how BMP4 regulates this process, which, if successful, will lead to improved methods of pharmacological prevention and treatment of this lethal complication of chronic lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Moore, Timothy M
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Johns Hopkins University
Internal Medicine/Medicine
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Yang, Kai; Jiang, Qian; Wang, Ziyi et al. (2015) Mutual inhibitory mechanisms between PPAR? and Hif-1?: implication in pulmonary hypertension. Receptors Clin Investig 2:e626
Yang, Kai; Lu, Wenju; Jiang, Qian et al. (2015) Peroxisome Proliferator-Activated Receptor ?-Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1-Dependent Mechanism. Am J Respir Cell Mol Biol 53:882-92
Wang, Jian; Fu, Xin; Yang, Kai et al. (2015) Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia-induced increase of TRPC expression in PASMCs. Cardiovasc Res 107:108-18
Wang, Yingfeng; Lu, Wenju; Yang, Kai et al. (2015) Peroxisome proliferator-activated receptor ? inhibits pulmonary hypertension targeting store-operated calcium entry. J Mol Med (Berl) 93:327-42
Yun, Xin; Chen, Yuqin; Yang, Kai et al. (2015) Upregulation of canonical transient receptor potential channel in the pulmonary arterial smooth muscle of a chronic thromboembolic pulmonary hypertension rat model. Hypertens Res 38:821-8
Yang, Kai; Lu, Wenju; Jia, Jing et al. (2015) Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels. Am J Physiol Cell Physiol 308:C869-78
Jiang, Qian; Fu, Xin; Tian, Lichun et al. (2014) NOX4 mediates BMP4-induced upregulation of TRPC1 and 6 protein expressions in distal pulmonary arterial smooth muscle cells. PLoS One 9:e107135
Zhang, Yi; Wang, Yingfeng; Yang, Kai et al. (2014) BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs. PLoS One 9:e112695
Wang, Jian; Chen, Yuqin; Lin, Chunyi et al. (2014) Effects of chronic exposure to cigarette smoke on canonical transient receptor potential expression in rat pulmonary arterial smooth muscle. Am J Physiol Cell Physiol 306:C364-73
Zhang, Zili; Wang, Jian; Chen, Sifan et al. (2014) Comparison of vegetarian diets and omnivorous diets on plasma level of HDL-c: a meta-analysis. PLoS One 9:e92609

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