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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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Quantitative IHC data of MMP2 (A) and MMP9 (B). The data are expressed as percent of positive labelling per tissue area. Representative WB for MMP2 (C) and MMP9 (D) and quantitative data of WB in different atrial tissues in patients in SR and in patients with AF. The data are expressed as ratios of either MMP2 or MMP9 expression levels to the actin content.
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fig04: Quantitative IHC data of MMP2 (A) and MMP9 (B). The data are expressed as percent of positive labelling per tissue area. Representative WB for MMP2 (C) and MMP9 (D) and quantitative data of WB in different atrial tissues in patients in SR and in patients with AF. The data are expressed as ratios of either MMP2 or MMP9 expression levels to the actin content.

Mentions: Expression levels of MMPs were analysed by IHC and WB analysis. Both methods demonstrated almost similar results (Fig. 4). According to quantitative IHC anaysis, MMP2 was significantly increased in RA appendages and free walls in AF groups as compared to SR (Fig. 4A), and demonstrated a tendency to be increased according to WB data (Fig. 4C). Quantification of MMP9 by IHC and WB showed that expression levels of MMP9 in AF groups were significantly higher than in SR groups (Fig. 4B and D).


Atrial extracellular matrix remodelling in patients with atrial fibrillation.

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

Quantitative IHC data of MMP2 (A) and MMP9 (B). The data are expressed as percent of positive labelling per tissue area. Representative WB for MMP2 (C) and MMP9 (D) and quantitative data of WB in different atrial tissues in patients in SR and in patients with AF. The data are expressed as ratios of either MMP2 or MMP9 expression levels to the actin content.
© Copyright Policy
Related In: Results  -  Collection

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

fig04: Quantitative IHC data of MMP2 (A) and MMP9 (B). The data are expressed as percent of positive labelling per tissue area. Representative WB for MMP2 (C) and MMP9 (D) and quantitative data of WB in different atrial tissues in patients in SR and in patients with AF. The data are expressed as ratios of either MMP2 or MMP9 expression levels to the actin content.
Mentions: Expression levels of MMPs were analysed by IHC and WB analysis. Both methods demonstrated almost similar results (Fig. 4). According to quantitative IHC anaysis, MMP2 was significantly increased in RA appendages and free walls in AF groups as compared to SR (Fig. 4A), and demonstrated a tendency to be increased according to WB data (Fig. 4C). Quantification of MMP9 by IHC and WB showed that expression levels of MMP9 in AF groups were significantly higher than in SR groups (Fig. 4B and D).

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