A minireview of E4BP4/NFIL3 in heart failure

Abstract

Heart failure (HF) remains a major cause of morbidity and mortality worldwide. The primary cause identified for HF is impaired left ventricular myocardial function, and clinical manifestations may lead to severe conditions like pulmonary congestion, splanchnic congestion, and peripheral edema. Development of new therapeutic strategies remains the need of the hour for controlling the problem of HF worldwide. Deeper insights into the molecular mechanisms involved in etiopathology of HF indicate the significant role of calcium signaling, autocrine signaling pathways, and insulin-like growth factor-1 signaling that regulates the physiologic functions of heart growth and development such as contraction, metabolism, hypertrophy, cytokine signaling, and apoptosis. In view of these facts, a transcription factor (TF) regulating the myriad of these signaling pathways may prove as a lead candidate for development of therapeutics. Adenovirus E4 promoter-binding protein (E4BP4), also known as nuclear-factor, interleukin 3 regulated (NFIL3), a type of basic leucine zipper TF, is known to regulate the signaling processes involved in the functioning of heart. The current review discusses about the expression, structure, and functional role of E4BP4 in signaling processes with emphasis on calcium signaling mechanisms, autocrine signaling, and insulin-like growth factor II receptor-mediated processes regulated by E4BP4 that may regulate the pathogenesis of HF. We propose that E4BP4, being the critical component for the regulation of the above signaling processes, may serve as a novel therapeutic target for HF, and scientific investigations are merited in this direction.

Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging

“…REV-ERBs protect Nampt expression by repressing E4bp4 , another transcriptional repressor that was only very recently found to target Nampt in the heart ( 18 ; Fig. 1 ), but has previously been implicated in heart health ( 34 , 35 ). The effect of E4BP4 repression on Nampt appears to be dominant to activation by the BMAL1:CLOCK heterodimer, given that the reduction persists through the induction of BMAL1 in the Rev-erbα/β knockout ( 18 ).…”

Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke

“…OTULIN has not been reported to function in HF, but it is closely related to the immuno-inflammatory pathway and the Wnt signaling pathway, as we found by GO annotation, and both these pathways are known to be involved in HF. NFIL3 is well known as a basic leucine zipper transcription regulator, which activates interleukin 3-induced signaling pathways in T cells and hematopoietic cells, and also works in diverse cell processes such as development and survival of immune cells and circadian rhythm control (Tamai et al, 2014;Velmurugan et al, 2018). Studies have not confirmed its role in HF or stroke.…”

“…Studies have not confirmed its role in HF or stroke. However, a review was devoted to elucidating the potential of NFIL3 as a new therapeutic target for HF due to its impact on several receptor-mediated processes which participate in pathogenesis of HF: calcium signaling, autocrine signaling, and insulin-like growth factor II signaling (Velmurugan et al, 2018). In addition, NFIL3 appears to be neuroprotective owing to its prosurvival and anti-apoptotic effects on neurons (Tamai et al, 2014).…”

miR‐203 accelerates apoptosis and inflammation induced by LPS via targeting NFIL3 in cardiomyocytes

“…34 A previous report indicated that NFIL3 played a central role in cardiovascular disease and regulated the pathogenesis of heart failure. 35 NFIL3 plays the role of a survival mediator in heart; overexpression of NFIL3 promotes cell survival and blocks apoptosis in cardiomyocytes. [36][37][38] Moreover, NFIL3 attenuated proinflammatory cytokines IL-5, IL-12, and IL-13 production, while augmented the expression of anti-inflammatory cytokine IL-10.…”

“…It was identified that NFIL3 could bind to the promoter of IL‐3 and serve as a transcriptional activator of IL‐3 . A previous report indicated that NFIL3 played a central role in cardiovascular disease and regulated the pathogenesis of heart failure . NFIL3 plays the role of a survival mediator in heart; overexpression of NFIL3 promotes cell survival and blocks apoptosis in cardiomyocytes .…”