Document Detail


Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency.
MedLine Citation:
PMID:  22764151     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: The shRNA-mediated loss of expression of the desmosomal protein plakophilin-2 leads to sodium current (I(Na)) dysfunction. Whether pkp2 gene haploinsufficiency leads to I(Na) deficit in vivo remains undefined. Mutations in pkp2 are detected in arrhythmogenic right ventricular cardiomyopathy (ARVC). Ventricular fibrillation and sudden death often occur in the 'concealed phase' of the disease, prior to overt structural damage. The mechanisms responsible for these arrhythmias remain poorly understood. We sought to characterize the morphology, histology, and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts and explore the relation between PKP2 abundance, I(Na) function, and cardiac electrical synchrony.
METHODS AND RESULTS: Hearts of PKP2-Hz mice were characterized by multiple methods. We observed ultrastructural but not histological or gross anatomical differences in PKP2-Hz hearts compared with wild-type (WT) littermates. Yet, in myocytes, decreased amplitude and a shift in gating and kinetics of I(Na) were observed. To further unmask I(Na) deficiency, we exposed myocytes, Langendorff-perfused hearts, and anaesthetized animals to a pharmacological challenge (flecainide). In PKP2-Hz hearts, the extent of flecainide-induced I(Na) block, impaired ventricular conduction, and altered electrocardiographic parameters were larger than controls. Flecainide provoked ventricular arrhythmias and death in PKP2-Hz animals, but not in the WT.
CONCLUSIONS: PKP2 haploinsufficiency leads to I(Na) deficit in murine hearts. Our data support the notion of a cross-talk between desmosome and sodium channel complex. They also suggest that I(Na) dysfunction may contribute to generation and/or maintenance of arrhythmias in PKP2-deficient hearts. Whether pharmacological challenges could help unveil arrhythmia risk in patients with mutations or variants in PKP2 remains undefined.
Authors:
Marina Cerrone; Maartje Noorman; Xianming Lin; Halina Chkourko; Feng-Xia Liang; Roel van der Nagel; Thomas Hund; Walter Birchmeier; Peter Mohler; Toon A van Veen; Harold V van Rijen; Mario Delmar
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-03
Journal Detail:
Title:  Cardiovascular research     Volume:  95     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-01-08     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  460-8     Citation Subset:  IM    
Affiliation:
Division of Cardiology, New York University School of Medicine, New York, NY, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Action Potentials
Animals
Anti-Arrhythmia Agents / pharmacology
Arrhythmogenic Right Ventricular Dysplasia / diagnosis,  genetics,  metabolism*,  pathology,  physiopathology
Disease Models, Animal
Electrocardiography
Flecainide / pharmacology
Genetic Predisposition to Disease
Haploinsufficiency*
Ion Channel Gating
Kinetics
Mice
Mice, Knockout
Myocytes, Cardiac / metabolism*,  ultrastructure
Perfusion
Phenotype
Plakophilins / deficiency*,  genetics
Sodium / metabolism*
Sodium Channels / drug effects,  metabolism*
Voltage-Gated Sodium Channel Blockers / pharmacology
Grant Support
ID/Acronym/Agency:
HL083422/HL/NHLBI NIH HHS; HL084583/HL/NHLBI NIH HHS; HL087226/HL/NHLBI NIH HHS; HL106632/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Pkp2 protein, mouse; 0/Plakophilins; 0/Sodium Channels; 0/Voltage-Gated Sodium Channel Blockers; 54143-55-4/Flecainide; 7440-23-5/Sodium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Emergency laparotomy helped the resection of an intralobar pulmonary sequestration with haemorrhagic...
Next Document:  Intercalated Disc Abnormalities, Reduced Na+ current density and Conduction Slowing in Desmoglein-2 ...