Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice

Abstract

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.

GCs-beta and B-arrestins Regulate Nrf2 via NR4As Productive Pathway Mediated by B-adrenergic for Anti-inflammation and Adopting Myocardial and Immune Functions

“…The NR4As pathway are having the role of controlling the extent of the inflammatory response for activating Estrogen productions through activating Acyl-COA-beta for promoting GCs-beta, B-arrestins synthesis (where NR4As are nuclear resonance or β-arrestin2 biosensors) which followed by Nrf2 production which activate ACE functions for Ang2-AT2 synthesis followed by VEGF-A productions "respectively" for anti-inflammatory growth and processes. The NR4A nuclear receptors sub-family (Nur77, Nurr1 and NOR-1) are emerging as important key in cardiac stress responses and adoptions; Where Nur77 seems to be a promising target in HF characterization and Therapy [6]. And in the heart itself the Nur77 is emerging as a key player in adverse cardiac remodeling [7].…”

Glucocorticoid-Beta Regulate B-Adrenergic and Nrf2 via NR4As Productive Pathway For Activating Anti-Inflammation Include Antioxidant Functions and Myocardial Immune Functions

“…That the Prolonged primary nuclear factor means dysfunction in some of followed activated steps for modulating proinflammation and GPCRs , that can be the result of causing mutation(due to accumulation) in pro-inflammation which will stimulate Tumor growth factor and will cause un-adopted growth which can lead to dilated cardiomyopathy. Where it is reported that prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice [8].…”

Vascular Endothelial Cell-Derived Exosomal Sphingosylphosphorylcholine Attenuates Myocardial Ischemia–Reperfusion Injury through NR4A2-Mediated Mitophagy

“…Nuclear receptor subfamily group A member 2 (NR4A2), also known as NURR1, is an orphan nuclear receptor belonging to the NR4A family of receptors [ 23 ]. Previous studies have suggested that NR4A2 regulates the pathogenesis of various heart diseases, including diabetic cardiomyopathy, cardiac hypertrophy, left ventricular dilation, and heart failure by modulating the autophagy flux, cardiac metabolism, and hemodynamics [ 24 , 25 , 26 ]. However, the roles of NR4A2 in myocardial I/R injury are controversial [ 27 , 28 ].…”