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(Circulation. 2003;108:1585.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Impaired VE-Cadherin/ß-Catenin Expression Mediates Endothelial Cell Degeneration in Dilated Cardiomyopathy

Romana Schäfer, PhD; Dietmar Abraham, PhD; Patrick Paulus, MS; Roland Blumer, PhD; Michael Grimm, MD; Johann Wojta, PhD; Seyedhossein Aharinejad, MD

From the Laboratory for Cardiovascular Research, Departments of Anatomy (R.S., D.A., P.P., R.B., S.A.), Cardio-Thoracic Surgery (M.G.), and Cardiology (J.W.), University of Vienna, Vienna, Austria.

Correspondence to S. Aharinejad, MD, Laboratory for Cardiovascular Research, Department of Anatomy, University of Vienna, Waehringerstrasse 13, A-1090 Vienna, Austria. E-mail ahas{at}univie.ac.at

Received April 23, 2002; de novo received May 14, 2003; accepted July 9, 2003.

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.

Methods and Results— The myocardial expression of VE-cadherin/ß-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/ß-catenin, and Ang-2. Analysis of tissue sections with similar rates of EC degeneration in both patient groups showed that VE-cadherin/ß-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/ß-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/ß-catenin, probably independent of VEGF. Targeting VE-cadherin might be of benefit to counteract the selective EC pathology in DCM.

Key Words: cardiomyopathy • endothelium • survival • molecular biology

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