MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2

Silicosis is a fatal pulmonary fibrotic disorder characterized by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. mir-449a is a potential mediator of many cellular processes, including cell proliferation, differentiation, and apoptosis. we hypothesized that mir-449a play a crucial role in the progression of pulmonary fibrogenesis. here, we described mir-449a as a new autophagy-regulated mirna. importantly, mir-449a expression was significantly decreased in lung tissues of mice with silica treatment, and it was similarly expressed in nih-3t3 and mrc-5 cells stimulated with tgf-β1. the activity of autophagy was inhibited in fibrotic lung tissues and tgf-β1-treated fibroblasts. to investigate the potential effect of mir-449a, we overexpressed mir-449a in mouse models and found that mir-449a significantly reduced both the distribution and severity of lung lesions induced by silica. in addition, mir-449a was observed to induce the activity of autophagy in vivo and in vitro. notably, bcl2 was identified as a target of mir-449a. bcl2 levels were decreased in nih-3t3 cells upon mir-449a overexpression. indeed, the bcl2 3′ utr contained functional mir-449a responsive sequences. furthermore, tgf-β1 was observed to increase the expression of bcl2 via the mapk/erk pathway. these results suggest that mir-449a is an important regulator of autophagy, as well as a novel endogenous suppressor of pulmonary fibrosis.