title: Anti-mitogenic effects of β-agonists and PGE2 on airway smooth muscle are PKA dependent.
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 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.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201-1075, USA.
authors.forename: Huandong
authors.initials: H
authors.lastname: Yan
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.forename: Anna M
authors.initials: AM
authors.lastname: Misior
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Miles
authors.forename: Himansh
authors.initials: H
authors.lastname: Saxena
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Riemer
authors.forename: Rodolfo M
authors.initials: RM
authors.lastname: Pascual
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Penn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000068299:Salmeterol Xinafoate; D013997:Time Factors; D014132:Trachea / Q000166:cytology; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol; D001993:Bronchodilator Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D004815:Epidermal Growth Factor; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D000068299:Salmeterol Xinafoate; C491526:PKIA protein, human
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