Reduced MicroRNA-19a causes constitutive high expression of PRMT1 and remodeling in asthma

Background: Asthma airway smooth muscle cells (ASMC) contribute significantly to airway remodeling by enhanced proliferation, migration, pro-inflammatory mediator secretion and extracellular matrix (ECM). In a rat model we described that protein arginine methyltransferase 1 (PRMT1) affects airway remodeling. Objectives: To identify the cause of increased PRMT1 expression in asthma. Methods: PRMT1 was localized by immunohistochemistry and by immunofluorescence. ASMC were isolated from lung tissue of healthy subjects and asthma patients and stimulated with PDGF-BB. PRMT1 activity was inhibited by AMI1, ERK1/2 MAPK by PD98059, and STAT1 by small interference (si) RNA. Bioinformatics analysis suggestedMAPK1 as a potential target of miR-19a, and ASMC were treated with either a miR-19a mimic or inhibitor. Results: PRMT1 was highly expressed in lung tissue sections of asthma patients, and in isolated ASMCs. Within 1 hour PDGF-BB significantly increased PRMT1 expression through ERK1/2 MAPK and STAT1 signaling in control, but not in asthmatic ASMC. The inhibition of ERK by PD diminished the ERK and STAT1 signaling cascade activation in asthma ASMCs. Additionally, asthmatic ASMCs lacked miR-19a and caused the consistently high expression of ERK and PRMT1. The inhibition of PRMT1 activity dampened ASMC remodeling by reducing proliferation, as well as collagen-1A1 and fibronectin synthesis. Conclusions: PRMT1 is a central regulator of ASMC remodeling and that the signaling sequence controlling its expression in primary human ASMC is PDGF-ERK-STAT1. Reduced miR-19a is the cause of constitutive elevated PRMT1 expression in asthma. Thus, PRMT1 is a potential new target for the therapy of remodeling in asthma.