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TRPV4‐mediated Ca 2+ influx promotes airway smooth muscle cell proliferation via NFATc3
Author(s) -
Zhao Limin,
Sullivan Michelle Nicole,
Gonzales Albert Louis,
Earley Scott
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.913.50
Subject(s) - nfat , chemistry , microbiology and biotechnology , agonist , cell growth , pharmacology , endocrinology , medicine , receptor , transcription factor , biochemistry , biology , gene
Bronchial asthma is a highly prevalent chronic respiratory disease with significant impact on human health. Airway remodeling due to proliferation of airway smooth muscle cells (ASMC) causes irreversible airflow obstruction during asthma, but the underlying molecular mechanisms are unclear. We hypothesized that Ca 2+ influx via TRPV4 contributes to ASMC proliferation. We find that the selective TRPV4 agonist GSK1016790A elicited concentration‐dependent Ca 2+ influx (EC 50 = 18.1±2.4 nM) in primary rat ASMC that was blocked by the TRPV4 antagonist HC067047 (500 nM). GSK1016790A enhanced ASMC proliferation (EC 50 =31.0±7.5 nM) whereas HC067047 (IC 50 =220 ±46 nM) had the opposite effect. Involvement of the Nuclear Factor of Activated T cells (NFAT), a Ca 2+ ‐activated transcription factor important for SMC proliferation, was examined. The calcineurin blocker cyclosporine (10 μM), and expression of the NFAT‐inhibiting peptide VIVIT attenuated GSK1016790A‐induced ASMC proliferation. In addition, GSK1016790A induced translocation of a cytoplasmic NFATc3‐GFP fusion protein to the nucleus of ASMC. Our findings show that Ca 2+ influx via TRPV4 induces proliferation of ASMC by activating NFATc3. Supported by HL091905.