The transcription factors (TFs) myocardin (MyoCD) and ETS Like-1 protein (Elk-1) competitively bind to serum response factor (SRF) and control myogenic- and mitogenic-related gene expression in smooth muscle, respectively. Their functions are therefore mutually inhibitory, which result in a contractile versus proliferative phenotype dichotomy. Airway smooth muscle cell (ASMC) phenotype alterations occur in various inflammatory airway diseases, promoting pathological remodelling and contributing to airflow obstruction. We characterized MyoCD and Elk-1 interactions and their roles in phenotype determination in human ASMCs. MyoCD overexpression in ASMCs increased smooth muscle gene expression, force generation, and partially restored the loss of smooth muscle protein associated with prolonged culturing, while inhibiting Elk-1 transcriptional activities and proliferation induced by epidermal growth factor (EGF). However, MyoCD overexpression failed to suppress these responses induced by fetal bovine serum (FBS) as FBS also upregulated SRF expression to a degree that allowed unopposed function of both TFs. Inhibition of the RhoA pathway reversed said SRF changes, allowing inhibition of Elk-1 by MyoCD overexpression and suppressing FBS-mediated contractile protein gene upregulation. Our study confirmed that MyoCD in increased abundance can competitively inhibit Elk-1 function. However, SRF upregulation permits a dual contractile-proliferative ASMC phenotype, anticipated to exacerbate pathological alterations, whereas therapies targeting SRF may inhibit both pathological ASMC proliferation and contractile protein gene expression.
