title: Impaired VE-cadherin/beta-catenin expression mediates endothelial cell degeneration in dilated cardiomyopathy.
abstract: BACKGROUND
  The cross-talk between vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang), and VE-cadherin coregulates endothelial cell (EC) survival. Cardiac expression of VEGF-A but not its receptor KDR is blunted in dilated cardiomyopathy (DCM). Whether VE-cadherin/Ang function is affected in DCM is unknown.
  
  
  RESULTS
  The myocardial expression of VE-cadherin/beta-catenin, Ang-1, Ang-2, and their receptor Tie-2 was examined in DCM, ischemic cardiomyopathy (ICM), and in control subjects through the use of real-time RT-PCR, Western blotting, and immunocytochemistry. EC degeneration was quantified by TEM. RNA interference against VE-cadherin and VEGF deprivation and stimulation were applied to cultured DCM myocardium and human microvascular ECs to examine the interplay between VEGF, VE-cadherin/beta-catenin, and Ang-2. Analysis of tissue sections with similar rates of EC degeneration in both patient groups showed that VE-cadherin/beta-catenin expression was downregulated in DCM only (P<0.05). Although Ang-1 was not changed, Ang-2 expression was downregulated and Tie-2 protein expression was upregulated both in DCM and ICM (P<0.05). The ratio of degenerated to normal ECs was significantly higher in DCM versus ICM (P<0.05). Targeted VE-cadherin gene silencing in cultured human ECs resulted in similar degenerative effects observed in myocardial ECs of DCM patients. In vitro experiments indicated that VE-cadherin/beta-catenin expression is independent of VEGF.
  
  
  CONCLUSIONS
  These results indicate for the first time that the EC survival is impaired in myocardium of patients with DCM involving VE-cadherin/beta-catenin, probably independent of VEGF. Targeting VE-cadherin might be of benefit to counteract the selective EC pathology in DCM.
authors.affiliation: Laboratory for Cardiovascular Research, Department of Anatomy, University of Vienna, Vienna, Austria.
authors.forename: Romana
authors.initials: R
authors.lastname: Schäfer
authors.forename: Dietmar
authors.initials: D
authors.lastname: Abraham
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.forename: Roland
authors.initials: R
authors.lastname: Blumer
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
authors.forename: Seyedhossein
authors.initials: S
authors.lastname: Aharinejad
mesh_terms: D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D042702:Angiopoietin-2; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009924:Organ Culture Techniques; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5
chemical_list: D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D000099152:Cadherin 5; C495270:CTNNB1 protein, human