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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 confocal images of matrix metalloproteinases (MMP2) labelling (green) in RFW in a patient in SR (A) and in a patient with AF (B). Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.(C and D) are confocal micrographs of a tissue section immunolabelled for SM-α-actin, MMP2 and f-actin from a patient with AF. Arrows indicate interstitial cells which are postive for SM-α-actin. Notice that these cells express MMP2 as shown by yellow colocalization colour. M, myocytes. Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.
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fig03: Representative confocal images of matrix metalloproteinases (MMP2) labelling (green) in RFW in a patient in SR (A) and in a patient with AF (B). Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.(C and D) are confocal micrographs of a tissue section immunolabelled for SM-α-actin, MMP2 and f-actin from a patient with AF. Arrows indicate interstitial cells which are postive for SM-α-actin. Notice that these cells express MMP2 as shown by yellow colocalization colour. M, myocytes. Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.

Mentions: By IHC, MMP2 and MMP9 were localized in the ECM, perivascular regions (Fig. 3A and B) and in interstitial cells, mostly in fibroblasts, as indicated by vimentin staining (data not shown) and myofibroblasts as shown using immunolabelling for SM-α-actin (Fig. 3C and D). As compared with patients in SR (Fig. 3A), MMP2 in AF groups was essentially enhanced and occupied larger ECM spaces (Fig 3B).


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 confocal images of matrix metalloproteinases (MMP2) labelling (green) in RFW in a patient in SR (A) and in a patient with AF (B). Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.(C and D) are confocal micrographs of a tissue section immunolabelled for SM-α-actin, MMP2 and f-actin from a patient with AF. Arrows indicate interstitial cells which are postive for SM-α-actin. Notice that these cells express MMP2 as shown by yellow colocalization colour. M, myocytes. Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.
© Copyright Policy
Related In: Results  -  Collection

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

fig03: Representative confocal images of matrix metalloproteinases (MMP2) labelling (green) in RFW in a patient in SR (A) and in a patient with AF (B). Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.(C and D) are confocal micrographs of a tissue section immunolabelled for SM-α-actin, MMP2 and f-actin from a patient with AF. Arrows indicate interstitial cells which are postive for SM-α-actin. Notice that these cells express MMP2 as shown by yellow colocalization colour. M, myocytes. Nuclei are stained blue with DAPI and f-actin is stained red with phalloidin conjugated with Alexa633.
Mentions: By IHC, MMP2 and MMP9 were localized in the ECM, perivascular regions (Fig. 3A and B) and in interstitial cells, mostly in fibroblasts, as indicated by vimentin staining (data not shown) and myofibroblasts as shown using immunolabelling for SM-α-actin (Fig. 3C and D). As compared with patients in SR (Fig. 3A), MMP2 in AF groups was essentially enhanced and occupied larger ECM spaces (Fig 3B).

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