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Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis.

Fu XX, Zhao N, Dong Q, Du LL, Chen XJ, Wu QF, Cheng X, Du YM, Liao YH - Int. J. Mol. Med. (2015)

Bottom Line: Western blot analysis was applied to quantify the expression of IL-17A.Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA).Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs).

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

ABSTRACT
Post-operative atrial fibrillation (AF) remains a common cause of morbidity. Increasing evidence indicates that inflammation and atrial fibrosis contribute to the pathogenesis of this condition. Interleukin (IL)-17A, a potent pro-inflammatory cytokine, has been implicated in the development of a number of cardiovascular diseases. However, its role in post-operative AF remains unknown. In the present study, sterile pericarditis (SP) was induced in rats by the epicardial application of sterile talc. AF was induced by transesophageal burst pacing. Western blot analysis was applied to quantify the expression of IL-17A. Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA). Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Histological analyses were performed to determine the extent of tissue inflammation and fibrosis. The rats with SP presented with a shorter refractoriness, a higher incidence and duration of AF, an enhanced susceptibility to developing AF, increased mRNA levels of AF-related pro-inflammatory cytokines (IL-6, IL-1β and TGF-β1), as well as marked atrial inflammation and fibrosis. The atrial IL-17A levels were elevated and correlated with the probability of developing AF. Treatment with anti-IL-17A monoclonal antibody decreased the levels of atrial IL-17A, prolonged refraction and markedly suppressed the development of AF. Simultaneously, inflammation and fibrosis were alleviated, which was further demonstrated by a decreased expression of AF-related pro-inflammatory cytokines, a downregulation in fibrosis-related mRNA expression (Col-1, Col-3 and α-SMA) and by the decreased activity of MMP-2/9 and TIMPs. Thus, the findings of our study indicate that IL-17A may play a pathogenic role in post-operative AF by inducing inflammation and fibrosis in rats with SP.

No MeSH data available.


Related in: MedlinePlus

Relative mRNA level of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA) in the atrial samples at 4 days after surgery. Data were normalized to the mRNA expression level of β-actin and are expressed relative to Sham. *P<0.05, **P<0.01 and ***P<0.001 vs. Sham; #P<0.05 and ##P<0.01 vs. IgG2a control. Sham, sham-operated rats; SP, rats with sterile pericarditis.
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f7-ijmm-36-01-0083: Relative mRNA level of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA) in the atrial samples at 4 days after surgery. Data were normalized to the mRNA expression level of β-actin and are expressed relative to Sham. *P<0.05, **P<0.01 and ***P<0.001 vs. Sham; #P<0.05 and ##P<0.01 vs. IgG2a control. Sham, sham-operated rats; SP, rats with sterile pericarditis.

Mentions: H&E staining revealed that treatment with the anti-IL-17A mAb resulted in a marked reduction in the infiltration of inflammatory cells into the atria compared to treatment with the isotype control IgG2a (Fig. 5A). Furthermore, the SP-induced increase in the mRNA expression of IL-6, IL-1β, TGF-β1 and IL-17A was significantly inhibited following treatment with anti-IL-17A mAb (Fig. 6A). The results obtained for IL-17A mRNA expression were confirmed at the protein level by western blot analysis and quantitative analysis (Fig. 6B and C). No changes were observed following treatment with the isotype contorl IgG2a. Notably, treatment with anti-IL-17A mAb markedly decreased the percentage area of fibrosis (Fig. 5B). Consistent with this observation, the mRNA expression of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA), which indicate the activation of extracellular matrix (ECM) synthesis, was significantly downregulated following treatment with anti-IL-17A mAb (Fig. 7).


Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis.

Fu XX, Zhao N, Dong Q, Du LL, Chen XJ, Wu QF, Cheng X, Du YM, Liao YH - Int. J. Mol. Med. (2015)

Relative mRNA level of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA) in the atrial samples at 4 days after surgery. Data were normalized to the mRNA expression level of β-actin and are expressed relative to Sham. *P<0.05, **P<0.01 and ***P<0.001 vs. Sham; #P<0.05 and ##P<0.01 vs. IgG2a control. Sham, sham-operated rats; SP, rats with sterile pericarditis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494571&req=5

f7-ijmm-36-01-0083: Relative mRNA level of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA) in the atrial samples at 4 days after surgery. Data were normalized to the mRNA expression level of β-actin and are expressed relative to Sham. *P<0.05, **P<0.01 and ***P<0.001 vs. Sham; #P<0.05 and ##P<0.01 vs. IgG2a control. Sham, sham-operated rats; SP, rats with sterile pericarditis.
Mentions: H&E staining revealed that treatment with the anti-IL-17A mAb resulted in a marked reduction in the infiltration of inflammatory cells into the atria compared to treatment with the isotype control IgG2a (Fig. 5A). Furthermore, the SP-induced increase in the mRNA expression of IL-6, IL-1β, TGF-β1 and IL-17A was significantly inhibited following treatment with anti-IL-17A mAb (Fig. 6A). The results obtained for IL-17A mRNA expression were confirmed at the protein level by western blot analysis and quantitative analysis (Fig. 6B and C). No changes were observed following treatment with the isotype contorl IgG2a. Notably, treatment with anti-IL-17A mAb markedly decreased the percentage area of fibrosis (Fig. 5B). Consistent with this observation, the mRNA expression of collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA), which indicate the activation of extracellular matrix (ECM) synthesis, was significantly downregulated following treatment with anti-IL-17A mAb (Fig. 7).

Bottom Line: Western blot analysis was applied to quantify the expression of IL-17A.Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA).Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs).

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

ABSTRACT
Post-operative atrial fibrillation (AF) remains a common cause of morbidity. Increasing evidence indicates that inflammation and atrial fibrosis contribute to the pathogenesis of this condition. Interleukin (IL)-17A, a potent pro-inflammatory cytokine, has been implicated in the development of a number of cardiovascular diseases. However, its role in post-operative AF remains unknown. In the present study, sterile pericarditis (SP) was induced in rats by the epicardial application of sterile talc. AF was induced by transesophageal burst pacing. Western blot analysis was applied to quantify the expression of IL-17A. Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA). Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Histological analyses were performed to determine the extent of tissue inflammation and fibrosis. The rats with SP presented with a shorter refractoriness, a higher incidence and duration of AF, an enhanced susceptibility to developing AF, increased mRNA levels of AF-related pro-inflammatory cytokines (IL-6, IL-1β and TGF-β1), as well as marked atrial inflammation and fibrosis. The atrial IL-17A levels were elevated and correlated with the probability of developing AF. Treatment with anti-IL-17A monoclonal antibody decreased the levels of atrial IL-17A, prolonged refraction and markedly suppressed the development of AF. Simultaneously, inflammation and fibrosis were alleviated, which was further demonstrated by a decreased expression of AF-related pro-inflammatory cytokines, a downregulation in fibrosis-related mRNA expression (Col-1, Col-3 and α-SMA) and by the decreased activity of MMP-2/9 and TIMPs. Thus, the findings of our study indicate that IL-17A may play a pathogenic role in post-operative AF by inducing inflammation and fibrosis in rats with SP.

No MeSH data available.


Related in: MedlinePlus