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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.


Synthesis and degradation of collagen in lung tissues of rats. A and B, Collagen type I (A) and type III (B) mRNA levels in lung tissues by real‐time polymerase chain reaction analysis. C and D, Protein expression of MMP‐13 (C) and TIMP‐1 (D) in lung tissues, detected by Western blotting. E, The ratio of MMP‐13/TIMP‐1 in lung tissues in rats of different groups. F, Activity of STAT3 in lung tissues of rats. 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; MMP‐13, matrix metalloproteinase 13; SO2, sulfur dioxide; STAT3, signal transducer and activator of transcription 3; TIMP‐1, tissue inhibitors of MMP‐1.
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jah31819-fig-0002: Synthesis and degradation of collagen in lung tissues of rats. A and B, Collagen type I (A) and type III (B) mRNA levels in lung tissues by real‐time polymerase chain reaction analysis. C and D, Protein expression of MMP‐13 (C) and TIMP‐1 (D) in lung tissues, detected by Western blotting. E, The ratio of MMP‐13/TIMP‐1 in lung tissues in rats of different groups. F, Activity of STAT3 in lung tissues of rats. 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; MMP‐13, matrix metalloproteinase 13; SO2, sulfur dioxide; STAT3, signal transducer and activator of transcription 3; TIMP‐1, tissue inhibitors of MMP‐1.

Mentions: Because synthesis of collagen types I and III depends on procollagen mRNA expression, we examined the procollagen types I and III mRNA levels in lung tissue using real‐time PCR. The results demonstrated that procollagen types I and III mRNA expression in lung tissue increased in the monocrotaline group (P<0.05 for both) (Figure 2A and 2B). Compared with the monocrotaline group, procollagen types I and III mRNA mounted up further in the monocrotaline plus HDX group (P<0.05 for both) (Figure 2A and 2B) but was markedly reduced in the monocrotaline plus SO2 group (P<0.05 for both) (Figure 2A and 2B).


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
Synthesis and degradation of collagen in lung tissues of rats. A and B, Collagen type I (A) and type III (B) mRNA levels in lung tissues by real‐time polymerase chain reaction analysis. C and D, Protein expression of MMP‐13 (C) and TIMP‐1 (D) in lung tissues, detected by Western blotting. E, The ratio of MMP‐13/TIMP‐1 in lung tissues in rats of different groups. F, Activity of STAT3 in lung tissues of rats. 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; MMP‐13, matrix metalloproteinase 13; SO2, sulfur dioxide; STAT3, signal transducer and activator of transcription 3; TIMP‐1, tissue inhibitors of MMP‐1.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5121494&req=5

jah31819-fig-0002: Synthesis and degradation of collagen in lung tissues of rats. A and B, Collagen type I (A) and type III (B) mRNA levels in lung tissues by real‐time polymerase chain reaction analysis. C and D, Protein expression of MMP‐13 (C) and TIMP‐1 (D) in lung tissues, detected by Western blotting. E, The ratio of MMP‐13/TIMP‐1 in lung tissues in rats of different groups. F, Activity of STAT3 in lung tissues of rats. 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; MMP‐13, matrix metalloproteinase 13; SO2, sulfur dioxide; STAT3, signal transducer and activator of transcription 3; TIMP‐1, tissue inhibitors of MMP‐1.
Mentions: Because synthesis of collagen types I and III depends on procollagen mRNA expression, we examined the procollagen types I and III mRNA levels in lung tissue using real‐time PCR. The results demonstrated that procollagen types I and III mRNA expression in lung tissue increased in the monocrotaline group (P<0.05 for both) (Figure 2A and 2B). Compared with the monocrotaline group, procollagen types I and III mRNA mounted up further in the monocrotaline plus HDX group (P<0.05 for both) (Figure 2A and 2B) but was markedly reduced in the monocrotaline plus SO2 group (P<0.05 for both) (Figure 2A and 2B).

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.