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Hydrogen sulfide inhibits the development of atherosclerosis with suppressing CX3CR1 and CX3CL1 expression.

Zhang H, Guo C, Wu D, Zhang A, Gu T, Wang L, Wang C - PLoS ONE (2012)

Bottom Line: It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages.Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages.In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

ABSTRACT
Hydrogen sulfide, as a novel gaseous mediator, has been suggested to play a key role in atherogenesis. However, the precise mechanisms by which H(2)S affects atherosclerosis remain unclear. Therefore, the present study aimed to investigate the potential role of H(2)S in atherosclerosis and the underlying mechanism with respect to chemokines (CCL2, CCL5 and CX3CL1) and chemokine receptors (CCR2, CCR5, and CX3CR1) in macrophages. Mouse macrophage cell line RAW 264.7 or mouse peritoneal macrophages were pre-incubated with saline or NaHS (50 µM, 100 µM, 200 µM), an H(2)S donor, and then stimulated with interferon-γ (IFN-γ) or lipopolysaccharide (LPS). It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages. Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages. The inhibitory effect of H(2)S on CX3CR1 and CX3CL1 expression was mediated by modulation of proliferators-activated receptor-γ (PPAR-γ) and NF-κB pathway. Furthermore, male apoE(-/-) mice were fed a high-fat diet and then randomly given NaHS (1 mg/kg, i.p., daily) or DL-propargylglycine (PAG, 10 mg/kg, i.p., daily). NaHS significantly inhibited aortic CX3CR1 and CX3CL1 expression and impeded aortic plaque development. NaHS had a better anti-atherogenic benefit when it was applied at the early stage of atherosclerosis. However, inhibition of H(2)S formation by PAG increased aortic CX3CR1 and CX3CL1 expression and exacerbated the extent of atherosclerosis. In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo. In conclusion, these data indicate that H(2)S hampers the progression of atherosclerosis in fat-fed apoE(-/-) mice and downregulates CX3CR1 and CX3CL1 expression on macrophages and in lesion plaques.

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Effect of PAG on the expression of CX3CR1 in atherosclerotic plaques in fat-fed apoE−/− mice.(A) Representative immunohistochemical images were taken from BCA in mice with fat feeding and saline, mice with fat feeding and PAG treatment. Scale bar for histological images  =  100 µm. (B) BCA sections from mice with fat feeding and saline and mice with fat feeding and PAG treatment were quantified immunohistochemically for CX3CR1 positive staining. Results shown are the mean ± SEM (n = 6–8 animals in each group). *P<0.05, compared with mice with fat feeding and saline.
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pone-0041147-g009: Effect of PAG on the expression of CX3CR1 in atherosclerotic plaques in fat-fed apoE−/− mice.(A) Representative immunohistochemical images were taken from BCA in mice with fat feeding and saline, mice with fat feeding and PAG treatment. Scale bar for histological images  =  100 µm. (B) BCA sections from mice with fat feeding and saline and mice with fat feeding and PAG treatment were quantified immunohistochemically for CX3CR1 positive staining. Results shown are the mean ± SEM (n = 6–8 animals in each group). *P<0.05, compared with mice with fat feeding and saline.

Mentions: Immunohistochemistry revealed that CX3CR1 was widely expressed in macrophages and foam cells in atherosclerotic plaques (Figure 8A). Both early and delayed treatment with NaHS suppressed the expression of CX3CR1 in atherosclerotic plaques (Figure 8). Early NaHS treatment induced a greater reduction in the CX3CR1 expression in atherosclerotic plaques compared with delayed NaHS treatment (Figure 8). However, PAG treatment upregulated CX3CR1 expression in plaques (Figure 9). Furthermore, as shown in Figure 10 and 11, CX3CR1 staining predominantly colocalized in macrophages within plaques, suggesting that alterations in CX3CR1 expression in plaque lesions are mainly caused by macrophages and that H2S may directly act on plaque macrophages to lower CX3CR1 expression in vivo (Figure 8S, negative control for immunofluorescent staining).


Hydrogen sulfide inhibits the development of atherosclerosis with suppressing CX3CR1 and CX3CL1 expression.

Zhang H, Guo C, Wu D, Zhang A, Gu T, Wang L, Wang C - PLoS ONE (2012)

Effect of PAG on the expression of CX3CR1 in atherosclerotic plaques in fat-fed apoE−/− mice.(A) Representative immunohistochemical images were taken from BCA in mice with fat feeding and saline, mice with fat feeding and PAG treatment. Scale bar for histological images  =  100 µm. (B) BCA sections from mice with fat feeding and saline and mice with fat feeding and PAG treatment were quantified immunohistochemically for CX3CR1 positive staining. Results shown are the mean ± SEM (n = 6–8 animals in each group). *P<0.05, compared with mice with fat feeding and saline.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3399807&req=5

pone-0041147-g009: Effect of PAG on the expression of CX3CR1 in atherosclerotic plaques in fat-fed apoE−/− mice.(A) Representative immunohistochemical images were taken from BCA in mice with fat feeding and saline, mice with fat feeding and PAG treatment. Scale bar for histological images  =  100 µm. (B) BCA sections from mice with fat feeding and saline and mice with fat feeding and PAG treatment were quantified immunohistochemically for CX3CR1 positive staining. Results shown are the mean ± SEM (n = 6–8 animals in each group). *P<0.05, compared with mice with fat feeding and saline.
Mentions: Immunohistochemistry revealed that CX3CR1 was widely expressed in macrophages and foam cells in atherosclerotic plaques (Figure 8A). Both early and delayed treatment with NaHS suppressed the expression of CX3CR1 in atherosclerotic plaques (Figure 8). Early NaHS treatment induced a greater reduction in the CX3CR1 expression in atherosclerotic plaques compared with delayed NaHS treatment (Figure 8). However, PAG treatment upregulated CX3CR1 expression in plaques (Figure 9). Furthermore, as shown in Figure 10 and 11, CX3CR1 staining predominantly colocalized in macrophages within plaques, suggesting that alterations in CX3CR1 expression in plaque lesions are mainly caused by macrophages and that H2S may directly act on plaque macrophages to lower CX3CR1 expression in vivo (Figure 8S, negative control for immunofluorescent staining).

Bottom Line: It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages.Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages.In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

ABSTRACT
Hydrogen sulfide, as a novel gaseous mediator, has been suggested to play a key role in atherogenesis. However, the precise mechanisms by which H(2)S affects atherosclerosis remain unclear. Therefore, the present study aimed to investigate the potential role of H(2)S in atherosclerosis and the underlying mechanism with respect to chemokines (CCL2, CCL5 and CX3CL1) and chemokine receptors (CCR2, CCR5, and CX3CR1) in macrophages. Mouse macrophage cell line RAW 264.7 or mouse peritoneal macrophages were pre-incubated with saline or NaHS (50 µM, 100 µM, 200 µM), an H(2)S donor, and then stimulated with interferon-γ (IFN-γ) or lipopolysaccharide (LPS). It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages. Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages. The inhibitory effect of H(2)S on CX3CR1 and CX3CL1 expression was mediated by modulation of proliferators-activated receptor-γ (PPAR-γ) and NF-κB pathway. Furthermore, male apoE(-/-) mice were fed a high-fat diet and then randomly given NaHS (1 mg/kg, i.p., daily) or DL-propargylglycine (PAG, 10 mg/kg, i.p., daily). NaHS significantly inhibited aortic CX3CR1 and CX3CL1 expression and impeded aortic plaque development. NaHS had a better anti-atherogenic benefit when it was applied at the early stage of atherosclerosis. However, inhibition of H(2)S formation by PAG increased aortic CX3CR1 and CX3CL1 expression and exacerbated the extent of atherosclerosis. In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo. In conclusion, these data indicate that H(2)S hampers the progression of atherosclerosis in fat-fed apoE(-/-) mice and downregulates CX3CR1 and CX3CL1 expression on macrophages and in lesion plaques.

Show MeSH
Related in: MedlinePlus