TGF-beta1 pathway activation and adherens junction molecular pattern in nonsyndromic mitral valve prolapse

Cardiovasc Pathol. 2015 Nov-Dec;24(6):359-67. doi: 10.1016/j.carpath.2015.07.009. Epub 2015 Aug 1.

Abstract

Aims: Dysregulation of the transforming growth factor beta (TGF-β) 1 pathway has been associated with either syndromic or isolated mitral valve (MV) prolapse due to myxoid degeneration (floppy MV). The activation of Smad receptor-mediated intracellular TGF-β pathway and its effect on adherens junction (AJ) molecular pattern of activated valvular interstitial cells (VICs) in MV prolapse are herein investigated.

Methods: Floppy MV leaflets were obtained from 30 patients (24 males, mean age 55.5±12.7 years) who underwent surgical repair, and 10 age- and sex-matched Homograft Tissue Bank samples served as controls. MV leaflet cellular and extracellular matrix composition, including collagen I and III, was evaluated by histology and transmission electron microscopy. Smad2 active phosphorylated form (p-Smad2), α-smooth muscle actin (α-SMA), and junctional proteins (N-cadherin, cadherin-11, β-catenin, plakoglobin, plakophilin-2) in VICs were assessed by immunohistochemistry and immunofluorescence and confirmed by immunoblotting. Quantitative real-time polymerase chain reaction was carried out for components of TGF-β pathway cascade and filamin A (FLN-A).

Results: Floppy MV leaflets were thicker (P<.001) and had higher α-SMA+ cell density (P=.002) and collagen III expression (P<.001) than controls. Enhanced p-Smad2 nuclear immunoreactivity (P<.001) and TGF-β1 gene (P=.045), TIMP1 (P=.020), and CTGF (P=.047) expression but no differences in FLN-A and total Smad2 gene expression levels were found between floppy MV and controls. Higher expression of cadherin-11, either exclusively or in colocalization with N-cadherin, and aberrant presence of plakophilin-2 at the AJ were found in floppy MV vs.

Conclusions: TGF-β1 pathway activation in nonsyndromic MV prolapse induces VICs differentiation into contractile myofibroblasts and is associated with changes in the molecular pattern of the AJ, with increased cadherin-11 and aberrant plakophilin-2 expression. AJ reinforcement might promote latent TGF-β1 activation leading to extracellular matrix remodeling in floppy MV.

Keywords: Adherens junction; Mitral valve prolapse; TGF-β activation; Valvular interstitial cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Adherens Junctions / chemistry*
  • Adherens Junctions / ultrastructure
  • Adult
  • Aged
  • Cadherins / analysis
  • Case-Control Studies
  • Cell Transdifferentiation
  • Collagen Type I / analysis
  • Collagen Type III / analysis
  • Desmoplakins / analysis
  • Extracellular Matrix / chemistry
  • Female
  • Filamins / genetics
  • Humans
  • Male
  • Middle Aged
  • Mitral Valve / chemistry*
  • Mitral Valve / surgery
  • Mitral Valve / ultrastructure
  • Mitral Valve Prolapse / genetics
  • Mitral Valve Prolapse / metabolism*
  • Mitral Valve Prolapse / pathology
  • Mitral Valve Prolapse / surgery
  • Myofibroblasts / chemistry*
  • Myofibroblasts / ultrastructure
  • Phenotype
  • Phosphorylation
  • Plakophilins / analysis
  • Signal Transduction
  • Smad2 Protein / analysis
  • Transforming Growth Factor beta1 / analysis*
  • Transforming Growth Factor beta1 / genetics
  • beta Catenin / analysis
  • gamma Catenin

Substances

  • ACTA2 protein, human
  • Actins
  • CTNNB1 protein, human
  • Cadherins
  • Collagen Type I
  • Collagen Type III
  • Desmoplakins
  • FLNA protein, human
  • Filamins
  • JUP protein, human
  • PKP2 protein, human
  • Plakophilins
  • SMAD2 protein, human
  • Smad2 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • beta Catenin
  • gamma Catenin