Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-β/Smad pathway in vascular smooth muscle cells

Abstract

The study was designed to investigate the role of endogenous sulfur dioxide (SO ₂) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO ₂ synthase aspartate aminotransferase (AAT) 1 or 2 increased SO ₂ levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-β1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-β1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-β receptor (TβRI) and Smad2/3 in TGF-β1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-β1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 μM SO ₂ blocked AAT deficiency-aggravated collagen accumulation in TGF-β1-stimulatd VSMCs, while no inhibition was observed at 100 μM ethyl pyruvate. These findings indicated that endogenous SO ₂ alleviated collagen remodeling by controlling TGF-β1/TβRI/Smad2/3-mediated modulation of collagen synthesis and degradation.