Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway.

Jia Liu,Zhenzhen Li,Jie Du,Junbao Du,Wen Yu,Chaoshu Tang,Cuiping Liu,Yaqian Huang,Hongfang Jin,Selena Chen,Xiaohui Li,Yanqiu Zhang,Yan Liu

doi:10.1038/srep21112

Abstract

The aim of the study was to investigate the role of endogenous sulfur dioxide (SO2)/ aspartate aminotransferase 1 (AAT1) pathway in stretch-induced excessive collagen expression and its mechanism. The mechanical stretch downregulated SO2/AAT1 pathway and increased collagen I and III protein expression. Importantly, AAT1 overexpression blocked the increase in collagen I and III expression, transforming growth factor-β1 (TGF- β1) expression and phosphorylation of Smad2/3 induced by stretch, but AAT1 knockdown mimicked the increase in collagen I and III expression, TGF- β1 expression and phosphorylation of Smad2/3 induced by stretch. Mechanistically, SB431542, a TGF-β1/Smad2/3 inhibitor, eliminated excessive collagen I and III accumulation induced by AAT1 knockdown, stretch or stretch plus AAT1 knockdown. In a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation, AAT1 expression and SO2 content in lung tissues of rat were reduced in shunt rats with high pulmonary blood flow. Supplement of SO2 derivatives inhibited activation of TGF- β1/Smad2/3 pathway and alleviated the excessive collagen accumulation in lung tissues of shunt rats. The results suggested that deficiency of endogenous SO2/AAT1 pathway mediated mechanical stretch-stimulated abnormal collagen accumulation via TGF-β1/Smad2/3 pathway.

Highlights

These results indicated that endogenous SO2/AAT1 pathway was downregulated in
Endogenous SO2/AAT1 pathway inhibited excessive collagen expression in primary pulmonary artery fibroblasts (PAFs) induced by mechanical stretch
There was no difference in collagen I and III protein expression between AAT1 group and AAT1 + stretch group (P all > 0.05; Fig. 2b). These results indicated that downregulation of endogenous SO2/AAT1 pathway might be an important pathogenesis of mechanical stretch-induced excessive collagen expression in PAFs

Summary

Introduction

As an emerging gasotransmitter following nitric oxide (NO), carbonic oxide (CO) and hydrogen sulfide (H2S), SO2 is known for its low molecular weight, continuous generation, quick diffusion and absorbance. These properties play vital physiological and pathological roles in vascular remodeling, including inhibiting the proliferation of vascular smooth muscle cells[16,17], promoting the apoptosis of vascular smooth muscle cells[18] and reducing abnormal deposition of collagen[16,19]. The present study was undertaken to examine if mechanical stretch could enhance collagen accumulation via the inhibition of the SO2/AAT1 pathway in pulmonary artery fibroblasts (PAFs) so as to better understand the possible mechanisms for high pulmonary blood flow-induced pulmonary vascular collagen remodeling

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Conclusion