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Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels
- Source :
- American Journal of Physiology-Cell Physiology. 308:C869-C878
- Publication Year :
- 2015
- Publisher :
- American Physiological Society, 2015.
-
Abstract
- 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.
- Subjects :
- Male
STAT3 Transcription Factor
Follistatin
medicine.medical_specialty
animal structures
Physiology
Hypertension, Pulmonary
Myocytes, Smooth Muscle
Primary Cell Culture
Bone Morphogenetic Protein 4
Pulmonary Artery
Biology
p38 Mitogen-Activated Protein Kinases
Pathogenesis
Transient receptor potential channel
Internal medicine
medicine
Animals
Calcium Signaling
Phosphorylation
Noggin
Hypoxia
TRPC
TRPC Cation Channels
Mitogen-Activated Protein Kinase 1
Extracellular Matrix Proteins
Mitogen-Activated Protein Kinase 3
Calcium-Binding Proteins
Proteins
Editorial Focus
Cell Biology
Janus Kinase 2
Hypoxia (medical)
medicine.disease
Store-operated calcium entry
Pulmonary hypertension
Rats
Cell biology
Endocrinology
Gene Expression Regulation
Bone morphogenetic protein 4
embryonic structures
Cytokines
medicine.symptom
Carrier Proteins
Subjects
Details
- ISSN :
- 15221563 and 03636143
- Volume :
- 308
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Cell Physiology
- Accession number :
- edsair.doi.dedup.....84470ddff2b198be5202eb4a10964375