|Ph.D Student||Koren Lilach|
|Subject||The Role of Transcription Factor ATF3 in Cardiac Hypertrophy|
|Department||Department of Medicine||Supervisor||Professor Ami Aronheim|
|Full Thesis text|
The heart responds to pressure overload by adaptive changes. However, if stress is sustained, the adaptive response turns into maladaptive. Changes as a result of prolonged stress are known as "cardiac remodeling" which may lead to heart failure.
Cardiac remodeling is dependent on combinatorial activity of transcription factors resulting in enlargement of the heart- hypertrophy. The exact molecular mechanisms responsible for cardiac enlargement are not well understood, but understanding them is crucial for the development of novel treatments.
In our lab we work on JDP2 and ATF3-members of the bZIP family of transcription factors and their influence on cardiac remodeling.
JDP2 protein is homologous to ATF3 and share 90% homology within the bZIP domain which is responsible for dimerization and DNA binding.
ATF3 is an immediate early gene, its basal expression is low in most cell types but increases upon induction by a wide variety of extracellular signals. ATF3 expression following stress is transient mainly due to ATF3 auto-inhibitory activity. Interestingly, JDP2 is able to repress ATF3 transcription through the same auto-regulatory site. Thus, JDP2 is responsible to maintain low basal levels of ATF3 expression in the absence of stress stimuli. Here we describe that upon stress stimuli JDP2 undergoes phosphorylaytion on threonine 148 which results in its protein degradation and expression of ATF3.
It was shown in our lab that JDP2 cardiac expression resulted in atrial enlargement, conduction defects and lethal phenotype. As a basis of my research thesis, we hypothesized that ATF3, also promotes cardiac hypertrophy.
We generated an ATF3 transgenic mouse strain over expressing ATF3 specifically in the heart. We were able to demonstrate that ATF3 over expression in cardiomyocytes is sufficient to promote cardiac hypertrophy. Consistently, we showed that mice with whole body ATF3-KO display significant reduced hypertrophy following exposure to pressure overload. We found that ATF3 expression is transient during the course of PE infusion.
We sought to prove that ATF3 expression in non-cardiac cells may express ATF3 and mediate the maladaptive cardiac remodeling processes in the heart.
Indeed, we found that bone marrow derived from ATF3-KO mice showed reduced cardiac hypertrophy as compared with Wt bone marrow. We also identified a unique ATF3 dependent cross-talk between cardiomyocytes and macrophages that is necessary to promote cardiac remodeling. This cross-talk occurs in an ATF3 dependent manner. We found that PE infusion induces the expression of IFNg. IFNg induces CXCL10 which in turn binds to the CXCR3 and induces maladaptive cardiac remodeling. Interestingly, all the components of the IFNg-CXCL10-CXCR3 axis are dependent on ATF3 transcription and therefore, in the absence of ATF3 this maladaptive axis is downregulated.
Lastly, we found that JDP2 also reduced pressure overload induced cardiac hypertrophy and a double knock out of both JDP2 and ATF3 resulted in an initial cardiac growth but following pressure overload seemed to protect these mice from maladaptive cardiac hypertrophy.
My thesis study describes a novel role for ATF3 in pressure overload induced cardiac hypertrophy. Ultimately, my thesis study will provide a novel therapeutic target towards suppressing heart failure.