Anti-mitogenic effects of beta-agonists and PGE(2) on airway smooth muscle are PKA dependent

作者：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^*

来源：The FASEB Journal, 2011, 25(1): 389-397.

DOI：10.1096/fj.10-164798

• airway remodeling
• asthma
• cell proliferation
• cyclic AMP
• G protein-coupled receptor

Inhaled beta-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. beta-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 role of PKA in mediating the effect of G(s)-coupled receptors on human ASM growth. Pretreatment of ASM cultures with beta-agonists albuterol, isoproterenol, or salmeterol (100 nM to 10 mu M) caused a significant (similar to 25-30%) inhibition of EGF-stimulated ASM thymidine 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 beta-agonists and PGE2 on airway smooth muscle are PKA dependent. FASEB J. 25, 389-397 (2011). www.fasebj.org

• 出版日期2011-1