טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentElhanani Ofer
SubjectThe Role and Regulation of Activating Transcription Factor 3
(ATF3) in the Myocardium in Health and Disease
DepartmentDepartment of Medicine
Supervisor Professor Ami Aronheim
Full Thesis textFull thesis text - English Version


Abstract

The heart is a muscular organ responsible for pumping blood through the circulatory system. The heart responds to various stimuli including pressure and volume overload as well as neurohormonal stimulation.

Heart failure affects approximately 1%-3% of people in western society. The development of heart failure is associated with cardiac hypertrophy and remodeling. Cardiac remodeling is a process involving a set of complex structural and functional changes in the myocardium in response to stress. These stressors include pressure and volume overload, Myocardial infarction, inflammatory diseases and idiopathic dilated cardiomyopathy.  Cardiac remodeling is an essential adaptive process designed to reduce ventricular wall and septal stress when faced with increased workload or injury. However, as this process persists, it becomes maladaptive. It leads to a decrease in cardiac function and eventually to heart failure. Neurohormonal systems such as the renin-angiotensin system and adrenergic receptors are important mediators of remodeling processes.

Basic leucine zipper (bZIP) proteins are members of a wide family of transcription factors. bZIP proteins can function as homo or hetero dimers and bind specific DNA sequences located at the regulatory region of numerous genes. Several lines of evidence suggest that bZIP transcription factors play a major role in myocardial remodeling.

In this study, we have identified the Activating Transcription Factor 3 (ATF3) as a direct transcriptional target for neurohormonal stimulation in the heart. ATF3 is an immediate early bZIP transcription factor found at the receiving end of many stress and growth stimuli.

ATF3 is induced in the heart in response to Angiotensin II (Ang II); Phenylephrine (PE)- a selective α1 adrenergic- receptor agonist; and isoproterenol (Iso.)- a β adrenergic receptor agonist. While ATF3 induction in response to PE and Iso occurred in both sides of the heart, its induction in response to Ang II was specific to the left chambers. Furthermore, our results show that the right chambers of the heart exhibit an overall impaired response to Ang II.

We have further characterized ATF3 induction in response to Ang II and showed it is dependent on both angiotensin receptor subtypes- AT1R and AT2R. We have also identified that EGFR activation and the AKT pathways are necessary for ATF3 induction in the heart.

Next, the role of ATF3 acute induction in the heart was studied. ATF3 KO mice acutely injected with PE exhibited reduced expression of proinflammatory transcriptional program.