Role of A-kinase anchoring proteins in airway smooth muscle phenotype modulation.

Airway remodeling is a main feature of asthma and is characterized by increased airway smooth muscle (ASM) mass, the latter known to contribute to airway hyperresponsiveness and lung function decrease. The platelet-derived growth factor (PDGF) is believed to enhance ASM proliferation and thereby airway remodeling. We reported earlier that cAMP inhibits PDGF-induced ASM phenotype modulation through its effectors exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA). Interestingly, A-kinase anchoring proteins (AKAPs) coordinate the communication between cAMP and its effectors via compartmentalization. Here we studied the role of AKAP-PKA interactions in PDGF-induced ASM phenotype modulation using the AKAP-PKA complex inhibitor peptide st-Ht31. Treatment with st-Ht31 increased basal DNA synthesis measured by [3H]-thymidine incorporation, but did not further enhance PDGF-induced DNA synthesis. St-Ht31 also increased the expression of the cell cycle regulator cyclinD1 and the phosphorylation of retinoblastoma protein under basal conditions but not under the PDGF conditions. In accordance, st-Ht31 lowered α-SMA gene expression under basal conditions, again leaving PDGF-induced α-SMA gene expression unchanged. Cell cycle studies using FACS analysis showed that st-Ht31 stimulated G1-G2 progression of ASM cells. In conclusion, AKAP-PKA interactions play an important role in regulation of ASM proliferation by compartmentalizing cAMP signaling.