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Research Article |
1 Center for Research on Reproduction and Women's Health, University of
Pennsylvania School of Medicine, 1355 Biomedical Research Building II/III, 421
Curie Blvd., Philadelphia, PA 19104, USA
2 Department of Pathology, University of Pennsylvania School of Medicine, 1355
Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104,
USA
* These authors contributed equally to this work
Present address: GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426,
USA
Author for correspondence (e-mail:
radice{at}mail.med.upenn.edu
)
Accepted 21 January 2002
The contractile force of the cardiomyocyte is transmitted through the adherens junction, a component of the intercalated disc, enabling the myocardium to function as a syncytium. The cadherin family of cell adhesion receptors, located in the adherens junction, interact homophilically to mediate strong cell-cell adhesion. Ectopic expression of cadherins is associated with changes in tumor cell behavior and pathology. To examine the effect of cadherin specificity on cardiac structure and function, we expressed either the epithelial cadherin, E-cadherin, or N-cadherin in the heart of transgenic mice. E-cadherin was localized to the intercalated disc structure in these animals similar to endogenous N-cadherin. Both N- and E-cadherin transgenic animals developed dilated cardiomyopathy. However, misexpression of E-cadherin led to earlier onset and increased mortality compared with N-cadherin mice. A dramatic decrease in connexin 43 was associated with the hypertrophic response in E-cadherin transgenic mice. Myofibril organization appeared normal although, vinculin, which normally localizes to the intercalated disc, was redistributed to the cytoplasm in the E-cadherin transgenic mice. Furthermore, E-cadherin induced cyclin D1, nuclear reduplication, and karyokinesis in the absence of cytokinesis, resulting in myocytes with two closely opposed nuclei. By contrast, N-cadherin overexpressing transgenic mice did not exhibit an increase in cyclin D1, suggesting that E-cadherin may provide a specific growth signal to the myocyte. This study demonstrates that modulation of cadherin-mediated adhesion can lead to dilated cardiomyopathy and that E-cadherin can stimulate DNA replication in myocytes normally withdrawn from the cell cycle.
Key words: Transgenic, Cell adhesion, Cardiac hypertrophy, Cyclin D1, DNA synthesis
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