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Sp1 Mediates a Therapeutic Role of MiR-7a/b in Angiotensin II-Induced Cardiac Fibrosis via Mechanism Involving the TGF-β and MAPKs Pathways in Cardiac Fibroblasts.

Li R, Xiao J, Qing X, Xing J, Xia Y, Qi J, Liu X, Zhang S, Sheng X, Zhang X, Ji X - PLoS ONE (2015)

Bottom Line: ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration.The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect.In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-β and MAPKs pathways.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.

ABSTRACT
MicroRNA-7a/b (miR-7a/b) protects cardiac myocytes from apoptosis during ischemia/reperfusion injury; however, its role in angiotensin II (ANG II)-stimulated cardiac fibroblasts (CFs) remains unknown. Therefore, the present study investigated the anti-fibrotic mechanism of miR-7a/b in ANG II-treated CFs. ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration. In addition, miR-7a/b also repressed the activation of TGF-β, ERK, JNK and p38 by ANG II. The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect. Further studies revealed that Sp1 also mediated miR-7a/b-regulated MMP expression and CF migration, as well as TGF-β and ERK activation. In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-β and MAPKs pathways.

No MeSH data available.


Related in: MedlinePlus

ANG II stimulated Sp1 and collagen I expression in CFs.A: Protein expression of Sp1 and collagen I in 100 nM ANG II-treated CFs at different time points. B: Protein expression of Sp1 and collagen I treated with different concentrations of ANG II for 24 h. C: normal untreated CFs. *p < 0.05, compared with control.
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pone.0125513.g001: ANG II stimulated Sp1 and collagen I expression in CFs.A: Protein expression of Sp1 and collagen I in 100 nM ANG II-treated CFs at different time points. B: Protein expression of Sp1 and collagen I treated with different concentrations of ANG II for 24 h. C: normal untreated CFs. *p < 0.05, compared with control.

Mentions: First, we examined the expression of Sp1 and collagen I in ANG II-treated CFs. The identification of CFs was presented as shown in S1 Fig ANG II (100 nM) effectively activated the expression of Sp1 and collagen I in a time-dependent manner (Fig 1A). Significant increases were detected as early as 12 h after the start of ANG II incubation, whereas a maximum effect was observed at 48 h. The dose response of ANG II was measured in the CFs at 24 h. The expression of Sp1 and collagen I increased gradually in a dose-dependent manner (Fig 1B). ANG II (100 nM) effectively increased Sp1 and collagen I expression at 24 h; therefore, this condition was used for subsequent experiments.


Sp1 Mediates a Therapeutic Role of MiR-7a/b in Angiotensin II-Induced Cardiac Fibrosis via Mechanism Involving the TGF-β and MAPKs Pathways in Cardiac Fibroblasts.

Li R, Xiao J, Qing X, Xing J, Xia Y, Qi J, Liu X, Zhang S, Sheng X, Zhang X, Ji X - PLoS ONE (2015)

ANG II stimulated Sp1 and collagen I expression in CFs.A: Protein expression of Sp1 and collagen I in 100 nM ANG II-treated CFs at different time points. B: Protein expression of Sp1 and collagen I treated with different concentrations of ANG II for 24 h. C: normal untreated CFs. *p < 0.05, compared with control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414609&req=5

pone.0125513.g001: ANG II stimulated Sp1 and collagen I expression in CFs.A: Protein expression of Sp1 and collagen I in 100 nM ANG II-treated CFs at different time points. B: Protein expression of Sp1 and collagen I treated with different concentrations of ANG II for 24 h. C: normal untreated CFs. *p < 0.05, compared with control.
Mentions: First, we examined the expression of Sp1 and collagen I in ANG II-treated CFs. The identification of CFs was presented as shown in S1 Fig ANG II (100 nM) effectively activated the expression of Sp1 and collagen I in a time-dependent manner (Fig 1A). Significant increases were detected as early as 12 h after the start of ANG II incubation, whereas a maximum effect was observed at 48 h. The dose response of ANG II was measured in the CFs at 24 h. The expression of Sp1 and collagen I increased gradually in a dose-dependent manner (Fig 1B). ANG II (100 nM) effectively increased Sp1 and collagen I expression at 24 h; therefore, this condition was used for subsequent experiments.

Bottom Line: ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration.The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect.In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-β and MAPKs pathways.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.

ABSTRACT
MicroRNA-7a/b (miR-7a/b) protects cardiac myocytes from apoptosis during ischemia/reperfusion injury; however, its role in angiotensin II (ANG II)-stimulated cardiac fibroblasts (CFs) remains unknown. Therefore, the present study investigated the anti-fibrotic mechanism of miR-7a/b in ANG II-treated CFs. ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration. In addition, miR-7a/b also repressed the activation of TGF-β, ERK, JNK and p38 by ANG II. The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect. Further studies revealed that Sp1 also mediated miR-7a/b-regulated MMP expression and CF migration, as well as TGF-β and ERK activation. In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-β and MAPKs pathways.

No MeSH data available.


Related in: MedlinePlus