Nuclear receptor Nur77 at the heart of cardiac disease modulation

Abstract

Heart failure (HF) is one of the leading causes of death in the Western world and is characterized by the constant interplay between the underlying cardiac insult, degree of myocardial dysfunction and the activity of compensatory neurohormonal mechanisms. Nur77 is a transcription factor that belongs to the NR4A family of nuclear receptors and is a well-established regulator of stress responses in the cardiovascular system. Especially in the context of atherosclerosis Nur77 has been studied extensively. However, the role of Nur77 in heart failure is far less well known. This thesis provides novel insights into the functional role of Nur77 in the various cell types that comprise the heart, extra-cardiac neurohormonal regulation mechanisms and during adverse cardiac remodeling caused by various cardiac insults. The key findings of this thesis include the identification of Nur77 as a regulator of cardiomyocyte calcium homeostasis and hypertrophy, cardiac myofibroblast differentiation, Neuropeptide Y signaling in the sympathoadrenal-cardiac axis, and the characterization of differential hematological phenotypes in two distinct mouse models of global Nur77 deficiency