MYH9 Inhibition Suppresses TGF-β1-Stimulated Lung Fibroblast-to-Myofibroblast Differentiation.

Xionghua Sun,Xiaogang Jiang,Mei Zhu,Xihua Chen

doi:10.3389/fphar.2020.573524

Abstract

Previous cDNA microarray results showed that MYH9 gene expression levels are increased in TGF-β1-stimulated lung fibroblast. Recently, our proteomic results revealed that the expression levels of MYH9 protein are notably upregulated in lung tissues of bleomycin-treated rats. However, whether MYH9 plays a critical role in the differentiation of fibroblast remains unclear. Herein, we demonstrated that TGF-β1 increased MYH9 expression, and siRNA-mediated knockdown of MYH9 and pharmacological inhibition of MYH9 ATPase activity remarkably repressed TGF-β1-induced lung fibroblast-to-myofibroblast differentiation. TGF-β1-stimulated MYH9 induction might be via ALK5/Smad2/3 pathway but not through noncanonical pathways, including p38 mitogen-activated kinase, and Akt pathways in lung fibroblasts. Our results showed that MYH9 inhibition suppressed TGF-β1-induced lung fibroblast-to-myofibroblast differentiation, which provides valuable information for illuminating the pathological mechanisms of lung fibroblast differentiation, and gives clues for finding new potential target for pulmonary fibrosis treatment.

Highlights

Fibroblasts are the primary mesenchymal cells in lung tissues, and their overactivation and differentiation into myofibroblasts are crucial to fibrosis progression induced by pulmonary toxic drugs or other lesions (Siani and Tirelli, 2014; Weng et al, 2014; Darby et al, 2016), which lead to the loss of respiratory function and death
TGF-β1 is well known as a profibrotic cytokine that promotes lung fibroblast-to-myofibroblast differentiation (Kim et al, 2018)
The α-smooth muscle actin (α-SMA) protein expression levels in different treatment groups were determined by Western blot analysis. n 3; scramble siRNA group vs. scramble siRNA group treated with TGF-β1: *p < 0.05; scramble siRNA group treated with TGF-β1 vs. MYH9 siRNA group treated with TGF-β1: #p < 0.05

Summary

Introduction

Fibroblasts are the primary mesenchymal cells in lung tissues, and their overactivation and differentiation into myofibroblasts are crucial to fibrosis progression induced by pulmonary toxic drugs or other lesions (Siani and Tirelli, 2014; Weng et al, 2014; Darby et al, 2016), which lead to the loss of respiratory function and death. The activated myofibroblasts secrete abundant collagen and fibronectin-containing extracellular matrix that accumulates and is remodeled into fibroblast foci (Scotton and Chambers, 2007). These functional changes mainly contribute to fibrosis development that is regulated by canonical and noncanonical TGF-β1 signaling (GharaeeKermani et al, 2009). Southern et al (Southern et al, 2016) thought MYH10 might be an effector of the profibrotic phenotype. These indicated that elucidating the function of muscle myosin and non-muscle

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Conclusion