Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels.
Abnormally elevated bone morphogenetic protein 4 (BMP4) expression and mediated signaling play a critical role in the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH). In this study, we investigated the expression level and functional significance of four reported naturally occurring BMP4 antagonists, noggin, follistatin, gremlin1, and matrix gla protein (MGP), in the lung and distal pulmonary arterial smooth muscle cell (PASMC). A 21-day chronic hypoxic (10% O2) exposure rat model was utilized, which has been previously shown to successfully establish experimental CHPH. Among the four antagonists, noggin, but not the other three, was selectively downregulated by hypoxic exposure in both the lung tissue and PASMC, in correlation with markedly elevated BMP4 expression, suggesting that the loss of noggin might account for the hypoxia-triggered BMP4 signaling transduction. Then, by using treatment of extrogenous recombinant noggin protein, we further found that noggin significantly normalized 1) BMP4-induced phosphorylation of cellular p38 and ERK1/2; 2) BMP4-induced phosphorylation of cellular JAK2 and STAT3; 3) hypoxia-induced PASMC proliferation; 4) hypoxia-induced store-operated calcium entry (SOCE), and 5) hypoxia-increased expression of transient receptor potential cation channels (TRPC1 and TRPC6) in PASMC. In combination, these data strongly indicated that the hypoxia-suppressed noggin accounts, at least partially, for hypoxia-induced excessive PASMC proliferation, while restoration of noggin may be an effective way to inhibit cell proliferation by suppressing SOCE and TRPC expression.
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
Kai
K
Yang
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
Wenju
W
Lu
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
Jing
J
Jia
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
Jie
J
Zhang
Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland.
Mingming
M
Zhao
Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
Sabrina
S
Wang
Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
Haiyang
H
Jiang
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
Lei
L
Xu
Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and jwang31@jhmi.edu wlu92@yahoo.com.
Jian
J
Wang
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D038681:Follistatin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097568:Matrix Gla Protein; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D038681:Follistatin; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011506:Proteins; D050796:STAT3 Transcription Factor; D050052:TRPC Cation Channels; D048051:p38 Mitogen-Activated Protein Kinases; D000097568:Matrix Gla Protein; D000099176:Noggin Protein; C525811:Bmp4 protein, rat; C107276:Grem1 protein, rat; C494088:Stat3 protein, rat; C492145:Trpc6 protein, rat; C096351:transient receptor potential cation channel, subfamily C, member 1; C507927:Jak2 protein, rat
TRPC; noggin; pulmonary hypertension; store-operated calcium entry