Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy

Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, Robert S. Ross

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

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 β1D 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.

Original languageEnglish (US)
Pages (from-to)7522-7537
Number of pages16
JournalMolecular and cellular biology
Volume27
Issue number21
DOIs
StatePublished - Nov 1 2007

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Vinculin
Dilated Cardiomyopathy
Sudden Death
Cardiac Myocytes
Gene Silencing
Muscle Cells
Genes
Adherens Junctions
Sarcolemma
Telemetry
Connexin 43
Connexins
Cadherins
Ventricular Tachycardia
Actin Cytoskeleton
Knockout Mice
Integrins
Adhesives
Cause of Death
Myocardium

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. / Zemljic-Harpf, Alice E.; Miller, Joel C.; Henderson, Scott A.; Wright, Adam T.; Manso, Ana Maria; Elsherif, Laila; Dalton, Nancy D.; Thor, Andrea K.; Perkins, Guy A.; McCulloch, Andrew D.; Ross, Robert S.

In: Molecular and cellular biology, Vol. 27, No. 21, 01.11.2007, p. 7522-7537.

Research output: Contribution to journalArticle

Zemljic-Harpf, AE, Miller, JC, Henderson, SA, Wright, AT, Manso, AM, Elsherif, L, Dalton, ND, Thor, AK, Perkins, GA, McCulloch, AD & Ross, RS 2007, 'Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy', Molecular and cellular biology, vol. 27, no. 21, pp. 7522-7537. https://doi.org/10.1128/MCB.00728-07
Zemljic-Harpf, Alice E. ; Miller, Joel C. ; Henderson, Scott A. ; Wright, Adam T. ; Manso, Ana Maria ; Elsherif, Laila ; Dalton, Nancy D. ; Thor, Andrea K. ; Perkins, Guy A. ; McCulloch, Andrew D. ; Ross, Robert S. / Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. In: Molecular and cellular biology. 2007 ; Vol. 27, No. 21. pp. 7522-7537.
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