MicroRNA-221 is overexpressed in the equine asthmatic airway smooth muscle and modulates smooth muscle cell proliferation

Abstract

Airway wall remodeling, including hyperplasia and hypertrophy of smooth muscle (ASM) cells leading to an increased smooth muscle mass, is considered central to asthma. However, molecular pathways responsible for ASM remodeling remain poorly understood. MicroRNAs (miRNAs) have emerged as key regulators of inflammatory and repair processes affecting the lungs and can downregulate protein expression by inhibiting target mRNA translation. We therefore hypothesized that miRNAs are involved in ASM remodeling in asthma by modulating ASM proliferation. We have analyzed the expression of miRNAs in bronchial smooth muscle from asthmatic horses during disease exacerbation and remission and from controls. Their involvement in ASM cell proliferation was then studied. Our results shown that miR-26a, miR-133, and miR-221 were upregulated in ASM from horses with asthma exacerbation compared with asthma remission and controls. MiR-221 induced cell hyperproliferation and reduced the expression of contractile gene markers in ASM cells. These changes were associated with the decreased mRNA expression of cell cycle regulatory genes (p53, p21, and p27). In conclusion, we demonstrated for the first time an upregulation of miR-221 in asthmatic airway smooth muscle and confirm the involvement of miR-221 in ASM cell proliferation by regulation of the cell cycle arrest genes. Targeting miR-221 network genes may represent a novel approach for the treatment of ASM remodeling in asthma.

Keywords: airway smooth muscle; asthma; cyclin-dependent kinase inhibitor; miR-221; myocardin.