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Published on: March 12, 2013
Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated
Alice E Zemljic-Harpf1, Joel C Miller, Scott A Henderson
1Department of Medicine, UCSD School of Medicine, La Jolla, California, USA.
Insights
Cardiac-specific inactivation of vinculin (Vcl) in mice caused sudden death due to ventricular tachycardia and defective conduction. Survivors developed dilated cardiomyopathy, highlighting Vcl
Area of Science:
- Cardiovascular Biology
- Cellular Adhesion
- Molecular Cardiology
Background:
- Vinculin (Vcl) is a key protein linking the actin cytoskeleton to the cell membrane.
- Its specific role in heart muscle cells (myocytes) and its contribution to cardiac function are not well understood.
- Understanding Vcl's function is crucial for cardiac health and disease.
Purpose of the Study:
- To investigate the function of vinculin in the myocardium.
- To determine the consequences of cardiac-myocyte-specific vinculin gene inactivation.
Main Methods:
- Development of a cardiac-myocyte-specific vinculin knockout mouse model (cVclKO) using Cre-loxP technology.
- Analysis of survival rates, cardiac function, and electrophysiology using telemetry and optical mapping.
- Ultrastructural analysis of heart tissue to examine cell-cell and cell-matrix adhesion structures.
Main Results:
- cVclKO mice exhibited a high incidence (49%) of sudden death before 3 months of age, primarily due to ventricular tachycardia.
- Defective myocardial conduction and mislocalization of junctional proteins (cadherin, beta1D integrin, connexin 43) were observed.
- Surviving cVclKO mice developed dilated cardiomyopathy and died before 6 months, with abnormal adherens junctions and intercalated disc dissolution.
Conclusions:
- Cardiac-specific vinculin is essential for maintaining normal myocardial structure and function.
- Loss of vinculin leads to severe cardiac arrhythmias, conduction defects, and ultimately heart failure.
- This study demonstrates vinculin's critical role in preserving cardiac cell-cell and cell-matrix adhesion.
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 beta1D 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.
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