Our long-term goal is to understand the relation between adhesion molecules and cardiac electrical function. We center on Plakophilin-2 (PKP2), a molecule classically defined as a component of the desmosome, though also known to cover functions beyond cell-cell adhesion. Mutations in PKP2 are recognized as the most common cause of familial arrhythmogenic right ventricular cardiomyopathy (ARVC) of known genetic origin. ARVC is characterized by fibrofatty infiltration, most commonly of right ventricular predominance, ventricular arrhythmias and sudden cardiac death in the young. RV predominance and the high incidence of life- threatening arrhythmias during the early stages of disease have puzzled investigators for years. The study of these features has been hampered by the lack of an animal model that reproduces the natural course of this condition. We have generated a cardiac-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2- cKO). To our knowledge, this is the first animal model with an arrhythmogenic cardiomyopathy of right ventricular predominance that results from PKP2 dysfunction.
Our aims are: 1: To characterize the arrhythmogenic phenotype following loss of PKP2 expression. Hypothesis: We propose that loss of PKP2 expression leads to a stage of arrhythmogenicity that precedes heart failure, characterized by asymmetric electrical remodeling of the ventricles. We further propose that such remodeling involves changes in electrical coupling and in sodium current properties, and that arrhythmias are triggered by dysregulation of Cai homeostasis. We postulate that this alteration is, in part, secondary to a) alterations in exon usage and b) changes in transcription of genes not previously linked to adhesion-related pathways and yet relevant to electrophysiology. 2: To characterize the nano-structural phenotype following loss of PKP2 expression. Hypothesis: We postulate that the recently described adhesion/excitability nodes (?mini-nodes of Ranvier?) at the ID act as points of convergence of two signaling platforms: One scaffolded by Ankyrin-G and the other, by PKP2. We further propose that loss of PKP2 expression leads to separation and eventual loss of the components of the adhesion/excitability node, including three key initiators of intracellular signaling cascades: CAMKII, PKC? and beta-catenin. We speculate that these changes are accompanied by asymmetrical (right vs left) changes in a) intercellular space dimensions and b) the anatomy of the dyad, thus contributing to the functional changes observed in the early-stage arrhythmogenic phenotype.

Public Health Relevance

Arrhythmias are a major cause of morbidity and mortality, at great economic and societal cost. We focus on the mechanisms for arrhythmias that depend on the abundance of a protein called plakophilin-2 (PKP2). Mutations in this protein cause an inherited arrhythmia disease called ?arrhythmogenic right ventricular cardiomyopathy.? We use modern physiology and microscopy methods to observe the anatomy of molecules in the scale of 10 millionths of an inch, and to study the arrhythmias of mouse hearts deficient in PKP2, as a way to better understand their mechanisms and potential for new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134328-03
Application #
9509517
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Balijepalli, Ravi C
Project Start
2016-08-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Sorgen, Paul L; Trease, Andrew J; Spagnol, Gaelle et al. (2018) Protein?Protein Interactions with Connexin 43: Regulation and Function. Int J Mol Sci 19:
Rivaud, Mathilde R; Agullo-Pascual, Esperanza; Lin, Xianming et al. (2017) Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes. J Am Heart Assoc 6:
Cerrone, Marina; Montnach, Jerome; Lin, Xianming et al. (2017) Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun 8:106