Damage to the mammalian heart is considered irreversible due to the inability of cardiac progenitor cells and differentiated cardiomyocytes to effectively repopulate the injured myocardium. It is believed that myofibril and cytoskeleton organization of differentiated cardiomyocytes hinder their ability to undergo cell division. It was recently demonstrated that differentiated rat cardiomyocytes induced by neuregulin-1 disassemble their sarcomeres in the midzone during karyokinesis and cytokinesis. A similar process has been shown to occur in adult zebrafish during heart regeneration after amputation. Alterations in sarcomeric proteins and cytoskeleton in injured heart suggest dedifferentiation of adult cardiomyocytes requires a transient reorganization of the cytoskeleton. However, the molecular mechanism(s) responsible for cytoskeleton remodeling in postnatal cardiomyocytes remain poorly understood. In this exploratory R21 application, we will directly investigate this mechanism by inducing deletion of the cytoskeletal regulator proteins, ?-catenins in the mouse heart. We provide evidence that adult cardiomyocytes reenter the cell cycle and undergo cytokinesis in the absence of ?-catenins. We hypothesize that loss of ?-catenins leads to cytoskeletal changes permissive for cell cycle reentry and cytokinesis of differentiated cardiomyocytes, thus representing a novel mechanism for cardiac regeneration. The following interrelated aims are proposed: (1) To define signal pathways that promote cardiomyocyte regeneration in a cardiac specific ?-catenin double knockout (DKO) model. In vivo and in vitro approaches will be used to examine the effects of specific signaling pathways on cardiomyocyte proliferation in the absence of ?-catenins. (2) To assess the de-differentiation of adult cardiomyocytes in the ?-catenin DKO heart. Cell lineage tracing will be performed to determine the cellular source of the increased cardiomyocytes in the ?-catenin DKO heart. (3) To determine the response of ?-catenin DKO mice to myocardial infarction. We will examine the cellular, molecular, and functional consequences that occur after myocardial infarction in the ?-catenin DKO compared with their littermate controls. We hypothesize that deletion of ?-catenins will promote cardiomyocyte proliferation leading to enhanced repair of damaged tissue, thus improving cardiac function after injury. The long term goal of this exploratory R21 proposal is to determine if interfering with the cytoskeletal proteins, ?-catenins, represents a potential therapy to enhance cardiac repair in heart failure patients.

Public Health Relevance

Cardiovascular disease remains the number one killer in the Western world. Accumulating evidence suggests that activation of the resident cardiac progenitor cells or local induced de-differentiation of existing adult cardiomyocytes can improve function of a failing heart. However, the mechanisms that regulate cardiomyocyte survival and proliferation remain poorly understood. We propose to investigate the effects of cytoskeleton remodeling on cardiomyocyte proliferation using a novel animal model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL111788-02
Application #
8509019
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2012-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$184,450
Indirect Cost
$65,450
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Li, Jifen; Gao, Erhe; Vite, Alexia et al. (2015) Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. Circ Res 116:70-9
Vite, Alexia; Radice, Glenn L (2014) N-cadherin/catenin complex as a master regulator of intercalated disc function. Cell Commun Adhes 21:169-79
Radice, Glenn L (2013) N-cadherin-mediated adhesion and signaling from development to disease: lessons from mice. Prog Mol Biol Transl Sci 116:263-89
Swope, David; Li, Jifen; Radice, Glenn L (2013) Beyond cell adhesion: the role of armadillo proteins in the heart. Cell Signal 25:93-100