Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor β1/Smad Pathway in Pulmonary Hypertensive Rats.

Background: We aimed to explore the role of endogenous sulfur dioxide (SO ₂ ) in pulmonary vascular collagen remodeling induced by monocrotaline and its mechanisms.
Methods and Results: A rat model of monocrotaline-induced pulmonary vascular collagen remodeling was developed and administered with l-aspartate-β-hydroxamate or SO ₂ donor. The morphology of small pulmonary arteries and collagen metabolism were examined. Cultured pulmonary arterial fibroblasts stimulated by transforming growth factor β1 (TGF-β1) were used to explore the mechanism. The results showed that in monocrotaline-treated rats, mean pulmonary artery pressure increased markedly, small pulmonary arterial remodeling developed, and collagen deposition in lung tissue and pulmonary arteries increased significantly in association with elevated SO ₂ content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l-aspartate-β-hydroxamate, an inhibitor of SO ₂ generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline-treated rats, and inhibition of SO ₂ in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO ₂ donor, however, alleviated pulmonary vascular collagen remodeling with inhibited collagen synthesis, augmented collagen degradation, and decreased TGF-β1 expression of pulmonary arteries. Mechanistically, overexpression of AAT1, a key enzyme of SO ₂ production, prevented the activation of the TGF-β/type I TGF-β receptor/Smad2/3 signaling pathway and abnormal collagen synthesis in pulmonary arterial fibroblasts. In contrast, knockdown of AAT1 exacerbated Smad2/3 phosphorylation and deposition of collagen types I and III in TGF-β1-treated pulmonary arterial fibroblasts.
Conclusions: Endogenous SO ₂ plays a protective role in pulmonary artery collagen accumulation induced by monocrotaline via inhibition of the TGF-β/type I TGF-β receptor/Smad2/3 pathway.
(© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)