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Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor β 1/Smad Pathway in Pulmonary Hypertensive Rats

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ABSTRACT

Background: We aimed to explore the role of endogenous sulfur dioxide (SO2) 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 SO2 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 SO2 content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l‐aspartate‐β‐hydroxamate, an inhibitor of SO2 generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline‐treated rats, and inhibition of SO2 in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO2 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 SO2 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 SO2 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.

No MeSH data available.


Changes in the NO/NOS2 system in lung tissues of rats. A, NO concentration in lung tissues of rats. B, Protein expression of NOS2 in lung tissues of rats, detected by Western blotting. Results are expressed as mean±SE, n=8. *P<0.05 compared with the control group; #P<0.05 compared with the MCT group. HDX indicates l‐aspartate‐β‐hydroxamate; MCT, monocrotaline; NO, nitric oxide; NOS2, nitric oxide synthase 2; SO2, sulfur dioxide; μmol/gpro, the content of NO (μmol) in 1 g protein.
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jah31819-fig-0010: Changes in the NO/NOS2 system in lung tissues of rats. A, NO concentration in lung tissues of rats. B, Protein expression of NOS2 in lung tissues of rats, detected by Western blotting. Results are expressed as mean±SE, n=8. *P<0.05 compared with the control group; #P<0.05 compared with the MCT group. HDX indicates l‐aspartate‐β‐hydroxamate; MCT, monocrotaline; NO, nitric oxide; NOS2, nitric oxide synthase 2; SO2, sulfur dioxide; μmol/gpro, the content of NO (μmol) in 1 g protein.

Mentions: To investigate the changes in NO generation, we detected NO concentration and NOS2 protein expression in lung tissues of rats. Results showed that NO concentration and NOS2 protein expression were decreased in monocrotaline‐treated rats compared with control rats (P<0.05 for both) (Figure 10). In monocrotaline‐treated rats with inhibition of SO2 generation, NO concentration and NOS2 protein expression in lung tissues were clearly increased (P<0.05 for both) (Figure 10); however, they did not change in monocrotaline‐treated rats when SO2 was supplied (P>0.05) (Figure 10).


Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor β 1/Smad Pathway in Pulmonary Hypertensive Rats
Changes in the NO/NOS2 system in lung tissues of rats. A, NO concentration in lung tissues of rats. B, Protein expression of NOS2 in lung tissues of rats, detected by Western blotting. Results are expressed as mean±SE, n=8. *P<0.05 compared with the control group; #P<0.05 compared with the MCT group. HDX indicates l‐aspartate‐β‐hydroxamate; MCT, monocrotaline; NO, nitric oxide; NOS2, nitric oxide synthase 2; SO2, sulfur dioxide; μmol/gpro, the content of NO (μmol) in 1 g protein.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121494&req=5

jah31819-fig-0010: Changes in the NO/NOS2 system in lung tissues of rats. A, NO concentration in lung tissues of rats. B, Protein expression of NOS2 in lung tissues of rats, detected by Western blotting. Results are expressed as mean±SE, n=8. *P<0.05 compared with the control group; #P<0.05 compared with the MCT group. HDX indicates l‐aspartate‐β‐hydroxamate; MCT, monocrotaline; NO, nitric oxide; NOS2, nitric oxide synthase 2; SO2, sulfur dioxide; μmol/gpro, the content of NO (μmol) in 1 g protein.
Mentions: To investigate the changes in NO generation, we detected NO concentration and NOS2 protein expression in lung tissues of rats. Results showed that NO concentration and NOS2 protein expression were decreased in monocrotaline‐treated rats compared with control rats (P<0.05 for both) (Figure 10). In monocrotaline‐treated rats with inhibition of SO2 generation, NO concentration and NOS2 protein expression in lung tissues were clearly increased (P<0.05 for both) (Figure 10); however, they did not change in monocrotaline‐treated rats when SO2 was supplied (P>0.05) (Figure 10).

View Article: PubMed Central - PubMed

ABSTRACT

Background: We aimed to explore the role of endogenous sulfur dioxide (SO2) in pulmonary vascular collagen remodeling induced by monocrotaline and its mechanisms.

Methods and results: A rat model of monocrotaline&#8208;induced pulmonary vascular collagen remodeling was developed and administered with l&#8208;aspartate&#8208;&beta;&#8208;hydroxamate or SO2 donor. The morphology of small pulmonary arteries and collagen metabolism were examined. Cultured pulmonary arterial fibroblasts stimulated by transforming growth factor &beta;1 (TGF&#8208;&beta;1) were used to explore the mechanism. The results showed that in monocrotaline&#8208;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 SO2 content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l&#8208;aspartate&#8208;&beta;&#8208;hydroxamate, an inhibitor of SO2 generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline&#8208;treated rats, and inhibition of SO2 in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO2 donor, however, alleviated pulmonary vascular collagen remodeling with inhibited collagen synthesis, augmented collagen degradation, and decreased TGF&#8208;&beta;1 expression of pulmonary arteries. Mechanistically, overexpression of AAT1, a key enzyme of SO2 production, prevented the activation of the TGF&#8208;&beta;/type I TGF&#8208;&beta; 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&#8208;&beta;1&ndash;treated pulmonary arterial fibroblasts.

Conclusions: Endogenous SO2 plays a protective role in pulmonary artery collagen accumulation induced by monocrotaline via inhibition of the TGF&#8208;&beta;/type I TGF&#8208;&beta; receptor/Smad2/3 pathway.

No MeSH data available.