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

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

doi:10.1128/mcb.00728-07

Cited by 186 publications

(214 citation statements)

References 94 publications

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“…This is the first report of loss-of-function VCL variants in DCM patients and is consistent with mouse studies that suggest that loss of VCL may lead to DCM. 30 It does not, however, refute the possibility that other variant types in this gene can lead to disease. Of note, loss-of-function VCL variants appear to be rare in the general population because only three such alleles (p.Asn220LysfsX21, p.Ala573HisfsX8, and p.Arg409X) have been found, each as singletons, in more than 8,250 chromosomes examined by the NHLBI ESP (accessed 13 October 2013).…”

Section: Loss-of-function Variants In Vinculin (Vcl) As An Emerging Rmentioning

confidence: 97%

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Pugh

Kelly

Gowrisankar

et al. 2014

Genetics in Medicine

307

282

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Section: Loss-of-function Variants In Vinculin (Vcl) As An Emerging Rmentioning

confidence: 97%

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Pugh

Kelly

Gowrisankar

et al. 2014

Genetics in Medicine

307

282

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“…These cVclKO mice developed two distinct phenotypes; a subset of them displayed ventricular tachycardia and died suddenly within the first 10 weeks of life, despite preserved systolic cardiac function. cVclKO mice that survived past this period, developed dilated cardiomyopathy and died of heart failure by 6 months of age (Zemljic-Harpf et al, 2007). Importantly, abnormal distribution of gap junctional protein Cx43 was detected within the intercalated discs of both Vcl +/2 and cVclKO mice when the mouse heart function was normal (Zemljic-Harpf et al, 2007;Zemljic-Harpf et al, 2004).…”

Section: Introductionmentioning

confidence: 94%

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Zemljic-Harpf

Godoy

Platoshyn

et al. 2014

Journal of Cell Science

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Vinculin (Vcl) links actin filaments to integrin-and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1, also known as TJP1) binds connexin-43 (Cx43, also known as GJA1), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Given that loss of Vcl from cardiomyocytes causes maldistribution of Cx43 and predisposes cardiomyocyte-specific Vcl-knockout mice with preserved heart function to arrhythmia and sudden death, we hypothesized that Vcl and ZO-1 interact and that loss of this interaction destabilizes gap junctions. We found that Vcl, Cx43 and ZO-1 colocalized at the intercalated disc. Loss of cardiomyocyte Vcl caused parallel loss of ZO-1 from intercalated dics. Vcl coimmunoprecipitated Cx43 and ZO-1, and directly bound ZO-1 in yeast two-hybrid studies. Excision of the Vcl gene in neonatal mouse cardiomyocytes caused a reduction in the amount of Vcl mRNA transcript and protein expression leading to (1) decreased protein expression of Cx43, ZO-1, talin, and b1D-integrin, (2) reduced PI3K activation, (3) increased activation of Akt, Erk1 and Erk2, and (4) cardiomyocyte necrosis. In summary, this is the first study showing a direct interaction between Vcl and ZO-1 and illustrates how Vcl plays a crucial role in stabilizing gap junctions and myocyte integrity.

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“…Maintenance of cardiac integrity also depends on the link between adjacent CMs mediated by the intercalated disks (ICD) (30,31). Although Tln is mainly localized at costameres, it has also been detected at low levels in ICDs (17).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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

Cited by 186 publications

References 94 publications

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

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