Abstract Rationale Aberrant contraction of airway smooth muscle (ASM), primarily driven by Gq-coupled G protein-coupled receptor signaling, is a hallmark of asthma. The most widely used bronchodilators, β2-adrenergic receptor (β2AR) agonists, counteract this process by activating Gs-mediated signaling pathways to induce ASM relaxation. However, chronic use of β-agonists results in receptor desensitization and a diminished therapeutic response. Identifying a novel target to relax ASM and induce bronchodilation is a clinical need. A previous study identified the critical role of histone deacetylase 11 (HDAC11) in regulating βAR signaling and function. Here, we investigated the role of HDAC11 in regulating ASM contractility and tested the hypothesis that pharmacological inhibition of HDAC11 inhibits ASM contraction. Methods Human ASM cultures were generated as per Panettieri et al. AJP 1989. We employed FT895, a small inhibitor, to modulate the activity of HDAC11 in ASM cells. Human ASM cells were pretreated with vehicle or FT895 (10 μM) for 1 h followed by treatment with histamine (1 μM) or methacholine (10 μM) for 10 min. Calcium mobilization and phosphorylation of MLC20 and MYPT1 were assessed upon agonist stimulation. Finally, the collagen gel contraction assay was used to assess the effect of FT895 on human ASM cell contraction. Treatment with isoproterenol (1 μM) for 10 min was used as a positive control. All the data are expressed as mean + SEM. Results FT895 treatment reduced histamine-stimulated calcium mobilization in human ASM cells by 37 ± 7% (n = 3). FT895 treatment inhibited histamine-induced MLC20 phosphorylation by 30 ± 6% and the MYPT1 phosphorylation by 20 ± 0.4%. Furthermore, FT895 inhibited methacholine-induced MLC20 phosphorylation by 35 ± 7% and the MYPT1 phosphorylation by 40 ± 2%. In collagen gel contraction assays, FT895 pretreatment inhibited histamine-induced gel contraction by 30 ± 3%. Conclusion The data presented here suggest that HDAC11 inhibition with FT895 treatment inhibits pro-contractile Gq signaling and contraction in ASM cells. Based on our previous study, the anti-contractile effect of HDAC11 inhibition is presumably mediated through activation of β2AR-PKA signaling. Collectively, HDAC11 inhibition represents a novel strategy to regulate ASM contraction in the management of asthma. This abstract is funded by: HL058506
Jannu et al. (Fri,) studied this question.