title: 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: We aimed to explore the role of endogenous sulfur dioxide (SO2) in pulmonary vascular collagen remodeling induced by monocrotaline and its mechanisms.
  
  
  
  A rat model of monocrotaline-induced pulmonary vascular collagen remodeling was developed and administered with l-aspartate-β-hydroxamate or SO2donor. 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 SO2content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l-aspartate-β-hydroxamate, an inhibitor of SO2generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline-treated rats, and inhibition of SO2in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO2donor, 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 SO2production, 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.
  
  
  
  Endogenous SO2plays 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.
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors: Wen
authors: W
authors: Yu
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors: Die
authors: D
authors: Liu
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors: Chen
authors: C
authors: Liang
authors: Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors: Todd
authors: T
authors: Ochs
authors: Department of Biochemistry and Cellular Biology, University of California, San Diego, La Jolla, CA.
authors: Stella
authors: S
authors: Chen
authors: Department of Biochemistry and Cellular Biology, University of California, San Diego, La Jolla, CA.
authors: Selena
authors: S
authors: Chen
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors: Shuxu
authors: S
authors: Du
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China.
authors: Chaoshu
authors: C
authors: Tang
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China yaqianhuang@126.com junbaodu1@126.com jinhongfang51@126.com.
authors: Yaqian
authors: Y
authors: Huang
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China yaqianhuang@126.com junbaodu1@126.com jinhongfang51@126.com.
authors: Junbao
authors: J
authors: Du
authors: Department of Pediatrics, Peking University First Hospital, Beijing, China yaqianhuang@126.com junbaodu1@126.com jinhongfang51@126.com.
authors: Hongfang
authors: H
authors: Jin
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000187:drug effects* / Q000378:metabolism; D013458:Sulfur Dioxide / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects* / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D051785:Smad Proteins; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D013458:Sulfur Dioxide; D016686:Monocrotaline; D003094:Collagen; D001219:Aspartate Aminotransferases
keywords: Smad2/3 signal; collagen deposition; pulmonary artery; sulfur dioxide; transforming growth factor β