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Molecular and Cellular Biology, November 2007, p. 7522-7537, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00728-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy{triangledown}

Alice E. Zemljic-Harpf,1,2 Joel C. Miller,1,2 Scott A. Henderson,3 Adam T. Wright,4 Ana Maria Manso,1,2 Laila Elsherif,1,2 Nancy D. Dalton,1 Andrea K. Thor,5 Guy A. Perkins,5 Andrew D. McCulloch,4 and Robert S. Ross1,2*

Department of Medicine, UCSD School of Medicine, La Jolla, California,1 Veterans Administration San Diego Healthcare System, San Diego, California,2 Department of Physiology and the Cardiovascular Research Laboratory, UCLA School of Medicine, Los Angeles, California,3 Department of Bioengineering, The Whitaker Institute for Biomedical Engineering, UCSD, La Jolla, California,4 National Center for Microscopy and Imaging Research Center for Research on Biological Structure, UCSD School of Medicine, San Diego, California5

Received 25 April 2007/ Returned for modification 17 June 2007/ Accepted 24 August 2007

Vinculin is a ubiquitously expressed multiliganded protein that links the actin cytoskeleton to the cell membrane. In myocytes, it is localized in protein complexes which anchor the contractile apparatus to the sarcolemma. Its function in the myocardium remains poorly understood. Therefore, we developed a mouse model with cardiac-myocyte-specific inactivation of the vinculin (Vcl) gene by using Cre-loxP technology. Sudden death was found in 49% of the knockout (cVclKO) mice younger than 3 months of age despite preservation of contractile function. Conscious telemetry documented ventricular tachycardia as the cause of sudden death, while defective myocardial conduction was detected by optical mapping. cVclKO mice that survived through the vulnerable period of sudden death developed dilated cardiomyopathy and died before 6 months of age. Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and ß1D integrin were reduced, and the gap junction protein connexin 43 was mislocalized to the lateral myocyte border. This is the first report of tissue-specific inactivation of the Vcl gene and shows that it is required for preservation of normal cell-cell and cell-matrix adhesive structures.

* Corresponding author. Mailing address: VA San Diego Healthcare System, 3350 La Jolla Village Drive, Cardiology Section, 111A, San Diego, CA 92161. Phone: (858) 642-1138. Fax: (858) 642-1199. E-mail: rross{at}ucsd.edu

{triangledown} Published ahead of print on 4 September 2007.

Molecular and Cellular Biology, November 2007, p. 7522-7537, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00728-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Palmer, S. M., Playford, M. P., Craig, S. W., Schaller, M. D., Campbell, S. L. (2009). Lipid Binding to the Tail Domain of Vinculin: SPECIFICITY AND THE ROLE OF THE N AND C TERMINI. J. Biol. Chem. 284: 7223-7231 [Abstract] [Full Text]  


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