This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vinculin and its muscle-splice variant metavinculin, link focal adhesions and cell-to-cell contact sites to the actin-cytoskeleton. We hypothesized that normal expression of vinculin isoforms would be essential for integrity of cardiomyocytes and preservation of normal cardiac function. We studied heterozygous vinculin knock-out mice (Vin +/-) that develop and breed normally.The Vin +/- mice displayed: 1) a 58% reduction of vinculin and a 63% reduction of metavinculin protein levels vs. wild-type littermates, 2) normal basal cardiac function and histology but abnormal electrocardiograms, intercalated disks and ICD-related protein distribution, 3) increased mortality following acute hemodynamic stress imposed by transverse aortic constriction (TAC), 4) cardiac dysfunction by 6 weeks post-TAC, 5) mis-alignment of alpha-actinin containing Z-lines and abnormal myocardial ultrastructure despite preserved cardiac function.This work is currently in press. Newer data suggests that the vinculin heterozygous KO mice have abnormal calcium handling. Since vinculin is accepted by some as a marker of T-tubules, we would like to assess these structures and more detailed analysis of intercalated disks in myocardial specimens from these animals.
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