Anti-mitogenic effects of β-agonists and PGE2on airway smooth muscle are PKA dependent

Huandong Yan, Deepak A. Deshpande, Anna M. Misior, Matthew C. Miles, Himansh Saxena, Ellen C. Riemer, Rodolfo M. Pascual, Reynold A. Panettieri, Raymond B. Penn

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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 role of PKA in mediating the effect of G s-coupled receptors on human ASM growth. Pretreatment of ASM cultures with β-agonists albuterol, isoproterenol, or salmeterol (100 nM to 10 μM) caused a significant (∼25-30%) inhibition of EGF-stimulated ASM thymidine incorporation and cell proliferation, whereas a much greater inhibition was observed from pretreatment with PGE2 (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 PGE2 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.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalFASEB Journal
Volume25
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Keywords

  • Airway remodeling
  • Asthma
  • Cell proliferation
  • Cyclic AMP
  • G protein-coupled receptor

Fingerprint

Dive into the research topics of 'Anti-mitogenic effects of β-agonists and PGE<sub>2</sub>on airway smooth muscle are PKA dependent'. Together they form a unique fingerprint.

Cite this