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

Abstract

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.