FOXO3A MODULATES CARDIAC REMODELING VIA INHIBITION OF MYOFIBROBLAST DIFFERENTIATION IN ACUTE MYOCARDIAL INFARCTION


Heart Failure and Cardiomyopathies

A1010
JACC March 17, 2015
Volume 65, Issue 10S

foxo3A modulAtes cArdIAc remodelIng vIA InhIBItIon of myofIBroBlAst 
dIfferentIAtIon In Acute myocArdIAl InfArctIon

Poster Contributions
Poster Hall B1
Monday, March 16, 2015, 9:45 a.m.-10:30 a.m.

Session Title: Energy Metabolism in Heart Failure
Abstract Category: 13.  Heart Failure and Cardiomyopathies: Basic
Presentation Number: 1250-179

Authors: Luise Holzhauser, Alexander Jenke, Konstantinos Savvatis, Mathias Grueger, Robert Schur, Dirk Westermann, Diana Lindner, 
Wolfgang Poller, Heinz-Peter Schultheiss, Carsten Skurk, Charite Berlin, Campus Benjamin Franklin, Department of Cardiology and 
Pulmonology, Berlin, Germany, Albert Einstein College of Medicine, Jacobi Medical Center, Department of Medicine, Bronx, NY, USA
Background: FOXO3a is a transcription factor and key regulator of cell differentiation, cycle and size and might be involved in regulation 
of cardiac remodeling following acute myocardial infarction. Myocardial adverse remodeling and scar formation are largely regulated by 
TGFβ/SMAD3 signaling leading to transdifferentiation of fibroblasts into myofibroblasts possibly inhibited by FOXO3a.
methods: Myofibroblast transdifferentiation markers were assessed following acute infarction in FOXO3-/- and WT mice (FVB) via 
permanent ligation of LAD. FOXO3a-/- and WT cardiac fibroblasts were investigated in transdifferentiation assays ex vivo. FOXO3a gene 
transfer was performed with gain of function adenoviral vectors. To test for a direct interaction between FOXO3a and SMAD3 western 
blotting and immunoprecipitation (IP) were used.
results: Reduced rates of ventricle perforation led to significantly higher survival rates in FOXO3a-/- mice compared to WT. At 3 and 14 
days post infarction myocardial expression of alpha smooth muscle actin (ASMA) and Collagen1A1 (Col1A1) was significantly enhanced 
in FOXO3a-/- mice associated with larger areas of fibrosis. In vitro cardiac fibroblasts isolated from FOXO3a-/- mice showed significantly 
enhanced expression of Col1A1 and ASMA 24 hours following stretch or TGF-β stimulation compared to WT cells. Moreover significantly 
higher protein expression of Col1A1 was shown in supernatants of FOXO3a -/- fibroblasts while FOXO3a gene-transfer dose-dependently 
downregulated Col1A1. FOXO3a gene transfer also led to significantly attenuated immunfluorescence staining for ASMA in cardiac 
fibroblasts. Interestingly IP showed direct interaction between FOXO3a and SMAD3a that was enhanced following activation of the 
transcription factor leading to diminished SMAD3 downstream gene expression.
conclusion:  We were able to show that FOXO3a regulates fibrosis and scar formation following myocardial infarction by direct inhibition of 
TGF- β regulated matrix remodeling via interaction with SMAD3. Thus the FOXO3a-SMAD3 axis might be of therapeutic interest to abate 
adverse myocardial remodeling.