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

Area of Science:

• Biochemistry
• Cell Biology
• Physiology

Background:

• Excessive collagen accumulation contributes to various fibrotic diseases.
• The role of endogenous sulfur dioxide (SO2) and aspartate aminotransferase 1 (AAT1) in mechanotransduction is not fully understood.
• Understanding the signaling pathways involved in mechanical stretch-induced collagen production is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the involvement of the endogenous sulfur dioxide (SO2)/aspartate aminotransferase 1 (AAT1) pathway in mechanical stretch-induced excessive collagen expression.
• To elucidate the underlying molecular mechanism, particularly the involvement of the transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway.

Main Methods:

• In vitro studies using cell cultures subjected to mechanical stretch.
• Manipulation of AAT1 expression (overexpression and knockdown).
• In vivo studies using a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation.
• Pharmacological inhibition of the TGF-β1/Smad2/3 pathway.

Main Results:

• Mechanical stretch downregulated the SO2/AAT1 pathway, leading to increased collagen I and III expression.
• AAT1 overexpression inhibited stretch-induced collagen, TGF-β1 expression, and Smad2/3 phosphorylation, while AAT1 knockdown mimicked these effects.
• Inhibition of the TGF-β1/Smad2/3 pathway abrogated excessive collagen accumulation.
• Reduced AAT1 expression and SO2 content were observed in a rat model of pulmonary vascular collagen accumulation.
• SO2 supplementation alleviated excessive collagen accumulation and inhibited the TGF-β1/Smad2/3 pathway in rats.

Conclusions:

• The endogenous SO2/AAT1 pathway plays a protective role against mechanical stretch-induced excessive collagen accumulation.
• Deficiency in the SO2/AAT1 pathway mediates mechanical stretch-stimulated abnormal collagen accumulation via the TGF-β1/Smad2/3 pathway.
• Targeting the SO2/AAT1 pathway or the TGF-β1/Smad2/3 pathway may offer therapeutic potential for fibrotic conditions characterized by excessive collagen deposition.