A-kinase anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

β2-agonists inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA) and exchange factor directly activated by cAMP (Epac) decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the current study we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from COPD patients. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of COPD patients, mRNA levels of AKAP5 and AKAP12 were decreased compared to lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of COPD GOLD stage II patients compared to control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in COPD patient lungs suggests that cigarette smoke-induced changes in AKAP5 and AKAP12 in COPD patients may affect efficacy of pharmacotherapy.