cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A.
OBJECTIVE
Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet-derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo-contractile phenotype, a process requiring activation of extracellular signal-regulated kinase (ERK) and p70(S6) Kinase (p70(S6K) ). The effects of cAMP-elevating agents on these processes is unknown. Here, we investigated the effects of cAMP elevation by prostaglandin E(2) (PGE(2) ) and the activation of the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (Epac) on PDGF-induced phenotype switching in bovine tracheal smooth muscle (BTSM).


METHODS
Effects of long-term treatment with the PGE(2) analogue 16,16-dimethyl-PGE(2) , the selective Epac activator, 8-pCPT-2'-O-Me-cAMP and the selective PKA activator, 6-Bnz-cAMP were assessed on the induction of a hypo-contractile, proliferative BTSM phenotype and on activation of ERK and p70(S6K) , both induced by PDGF.


RESULTS
Treatment with 16,16-dimethyl-PGE(2) inhibited PDGF-induced proliferation of BTSM cells and maintained BTSM strip contractility and contractile protein expression in the presence of PDGF. Activation of both Epac and PKA similarly prevented PDGF-induced phenotype switching and PDGF-induced activation of ERK. Interestingly, only PKA activation resulted in inhibition of PDGF-induced phosphorylation of p70(S6K) .


CONCLUSIONS
Our data indicate for the first time that both Epac and PKA regulated switching of ASM phenotype via differential inhibition of ERK and p70(S6K) pathways. These findings suggest that cAMP elevation may be beneficial in the treatment of long-term changes in airway disease.
Roscioni
Sara S
SS
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. s.s.roscioni@rug.nl
Dekkers
Bart G J
BG
Prins
Alwin G
AG
Menzen
Mark H
MH
Meurs
Herman
H
Schmidt
Martina
M
Maarsingh
Harm
H
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology
D010982:Platelet-Derived Growth Factor; D000242:Cyclic AMP; D019893:Ribosomal Protein S6 Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015064:16,16-Dimethylprostaglandin E2
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