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Atrial extracellular matrix remodelling in patients with atrial fibrillation.

Polyakova V, Miyagawa S, Szalay Z, Risteli J, Kostin S - J. Cell. Mol. Med. (2008)

Bottom Line: As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups.Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05).Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute for Heart and Lung Research, Core Lab for Molecular and Structural Biology, Bad Nauheim, Germany.

ABSTRACT

Unlabelled: Atrial fibrillation (AF) is the most frequent clinical arrhythmia. Atrial fibrosis is an important factor in initiating and maintaining AF. However, the collagen turnover and its regulation in AF has not been completely elucidated. We tested the hypothesis that the extracellular matrix changes are more severe in patients with permanent AF in comparison with those in patients in sinus rhythm (SR). Intraoperative biopsies from the right atrial appendages (RAA) and free walls (RFW) from 24 patients with AF undergoing a mini-Maze procedure and 24 patients in SR were investigated with qualitative and quantitative immunofluorescent and Western blot analyses. As compared with SR, all patients with AF exhibited dysregulations in collagen type I and type III synthesis/degradation. Tissue inhibitors of metalloproteinases (TIMP2) was significantly enhanced only in RAA-AF. As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05). The level of transforming growth factor (TGF)-beta1 was higher in AF than SR. Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05).

Conclusions: Atrial fibrosis in AF is characterized by severe alterations in collagen I and III synthesis/degradation associated with disturbed MMP/TIMP systems and increased levels of RECK. TGF-beta1 contributes to atrial fibrosis via TGF-beta1-Smad pathway by phosphorylating Smad2. These processes culminate in accumulations of fibrillar and non-fibrillar collagens leading to excessive atrial fibrosis and maintainance of AF.

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Representative immunofluorescent images of Reversion- inducing cysteinerich protein with Kazal motifs (RECK) labelling in RAA in patients in SR (A) and in patients with AF (B). Nuclei are stained blue with DAPI. Typical WB and quantitative WB data for RECK in different atrial tissues in patients in SR and in patients with AF (C).
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fig06: Representative immunofluorescent images of Reversion- inducing cysteinerich protein with Kazal motifs (RECK) labelling in RAA in patients in SR (A) and in patients with AF (B). Nuclei are stained blue with DAPI. Typical WB and quantitative WB data for RECK in different atrial tissues in patients in SR and in patients with AF (C).

Mentions: By IHC, RECK expression was found in patients of both AF and SR groups. The localization of RECK was confined mainly to interstitial cells or diffusely as a punctate labelling in the ECM (Fig. 6A and B). We did not find visually apparent differences in RECK expression in AF and SR groups except the observation that in SR groups RECK-positive staining was found in isolated ECM cells; whereas in AF groups more often diffuse positive spots or cell accumulations in the interstitium were observed. WB analysis revealed a significant increase in RECK expression levels only in RFW-AF group as compared to RAA-AF, RAA-SR and RFW-SR groups, respectively (Fig. 6C).


Atrial extracellular matrix remodelling in patients with atrial fibrillation.

Polyakova V, Miyagawa S, Szalay Z, Risteli J, Kostin S - J. Cell. Mol. Med. (2008)

Representative immunofluorescent images of Reversion- inducing cysteinerich protein with Kazal motifs (RECK) labelling in RAA in patients in SR (A) and in patients with AF (B). Nuclei are stained blue with DAPI. Typical WB and quantitative WB data for RECK in different atrial tissues in patients in SR and in patients with AF (C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823481&req=5

fig06: Representative immunofluorescent images of Reversion- inducing cysteinerich protein with Kazal motifs (RECK) labelling in RAA in patients in SR (A) and in patients with AF (B). Nuclei are stained blue with DAPI. Typical WB and quantitative WB data for RECK in different atrial tissues in patients in SR and in patients with AF (C).
Mentions: By IHC, RECK expression was found in patients of both AF and SR groups. The localization of RECK was confined mainly to interstitial cells or diffusely as a punctate labelling in the ECM (Fig. 6A and B). We did not find visually apparent differences in RECK expression in AF and SR groups except the observation that in SR groups RECK-positive staining was found in isolated ECM cells; whereas in AF groups more often diffuse positive spots or cell accumulations in the interstitium were observed. WB analysis revealed a significant increase in RECK expression levels only in RFW-AF group as compared to RAA-AF, RAA-SR and RFW-SR groups, respectively (Fig. 6C).

Bottom Line: As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups.Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05).Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute for Heart and Lung Research, Core Lab for Molecular and Structural Biology, Bad Nauheim, Germany.

ABSTRACT

Unlabelled: Atrial fibrillation (AF) is the most frequent clinical arrhythmia. Atrial fibrosis is an important factor in initiating and maintaining AF. However, the collagen turnover and its regulation in AF has not been completely elucidated. We tested the hypothesis that the extracellular matrix changes are more severe in patients with permanent AF in comparison with those in patients in sinus rhythm (SR). Intraoperative biopsies from the right atrial appendages (RAA) and free walls (RFW) from 24 patients with AF undergoing a mini-Maze procedure and 24 patients in SR were investigated with qualitative and quantitative immunofluorescent and Western blot analyses. As compared with SR, all patients with AF exhibited dysregulations in collagen type I and type III synthesis/degradation. Tissue inhibitors of metalloproteinases (TIMP2) was significantly enhanced only in RAA-AF. As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05). The level of transforming growth factor (TGF)-beta1 was higher in AF than SR. Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05).

Conclusions: Atrial fibrosis in AF is characterized by severe alterations in collagen I and III synthesis/degradation associated with disturbed MMP/TIMP systems and increased levels of RECK. TGF-beta1 contributes to atrial fibrosis via TGF-beta1-Smad pathway by phosphorylating Smad2. These processes culminate in accumulations of fibrillar and non-fibrillar collagens leading to excessive atrial fibrosis and maintainance of AF.

Show MeSH
Related in: MedlinePlus