טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAbu Sharki Soraya
SubjectATF3 Expression in Cardiomyocytes and Myofibroblasts
following Transverse Aortic Constriction
Displays Distinct Phenotypes
DepartmentDepartment of Medicine
Supervisor PROF. Ami Aronheim


Abstract

Activating transcription 3 (ATF3) is a member of the basic leucine zipper family of transcription factors. ATF3 is an immediate early gene expressed following various cellular stresses. ATF3 acts through binding to cyclic AMP response elements found in the promoters of key regulatory proteins that determine cell fate. In the heart, multiple cardiac stresses result in chronic ATF3 expression. Transgenic mice with ATF3 over-expression in cardiomyocytes express heart hypertrophy, cardiac fibrosis, cardiac dysfunction, and death clearly demonstrate that ATF3 serves a leading role in these ailments. In contrast, the use of ATF3 whole body knockout mice resulted non-conclusive results. The heart is composed of various cell types such as cardiomyocytes, fibroblasts, endothelial and immune cells. The question that we addressed in this study is whether ablation of ATF3 in unique cell types in the heart results in diverse cardiac phenotypes. ATF3-flox mice were crossed with αMHC and Postn specific promoters directing CRE expression and thus ATF3 ablation in cardiomyocytes and myofibroblast cells respectively. Mice were challenged with transverse aortic constriction (TAC) for eight weeks and heart function, ventricle weight, hypertrophic markers, fibrosis markers and ATF3 expression were assessed by qRT-PCR. The results of the study show that ATF3 deletion in cardiomyocytes followed by TAC resulted in reduced heart growth and a dampened fibrosis response while ATF3 ablation in myofibroblasts resulted in a reduced hypertrophic gene program. TAC-operation results in increased ATF3 expression in both myofibroblasts and cardiomyocytes, promoting a hypertrophic program and fibrotic cardiac growth, respectively.