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Anti‐mitogenic effects of β‐agonists and PGE 2 on airway smooth muscle are PKA dependent
Author(s) -
Yan Huandong,
Deshpande Deepak A.,
Misior Anna M.,
Miles Matthew C.,
Saxena Himansh,
Riemer Ellen C.,
Pascual Rodolfo M.,
Panettieri Reynold A.,
Penn Raymond B.
Publication year - 2011
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/fj.10-164798
Subject(s) - bronchoconstriction , protein kinase a , receptor , cell growth , chemistry , pi3k/akt/mtor pathway , medicine , endocrinology , pharmacology , microbiology and biotechnology , signal transduction , biology , kinase , asthma , biochemistry
Inhaled β‐agonists are effective airway smooth muscle (ASM)‐relaxing agents that help reverse bronchoconstriction in asthma, but their ability to affect the aberrant ASM growth that also occurs with asthma is poorly understood. β‐Agonists exhibit PKA‐dependent antimitogenic effects in several cell types. However, recent studies suggest that Epac, and not PKA, mediates the antimitogenic effect of cAMP in both ASM and fibroblasts. This study aims to clarify the roleof PKA in mediating the effect of G S ‐coupled receptors on human ASM growth. Pretreatmentof ASM cultures with β‐agonists albuterol, isoproterenol, or salmeterol (100 nM to 10 µM) caused a significant (‐25–30%) inhibition of EGF‐stimulated ASM thymi‐dine incorporation and cell proliferation, whereas a much greater inhibition was observed from pretreatment with PGE 2 (75–80%). However, all agents were ineffective in cells expressing GFP chimeras of either PKI (a PKA inhibitor) or a mutant PKA regulatory subunit relative to the control cells expressing GFP. The antimitogenic efficacy of PGE 2 in inhibiting control cultures was associated with greater ability to stimulate sustained PKA activation and greater inhibition of late‐phase promitogenic p42/p44 and PI3K activities. These findings suggest that therapeutic approaches enabling superior PKA activation in ASM will be most efficacious in deterring ASM growth.—Yan, H., Deshpande, D. A., Misior, A. M., Miles, M. C., Saxena, H., Riemer, E. C., Pascual, R. M., Panettieri, R. A., Penn. R. B. Anti‐mitogenic effects of β‐agonists and PGE 2 on airway smooth muscle are PKA dependent. FASEB J. 25, 389–397 (2011). www.fasebj.org