The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling

Abstract

<jats:p> Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of ERBB4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (Ang II) or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatio-temporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury. </jats:p>

Adipose/Connective Tissue From Thyroid-Associated Ophthalmopathy Uncovers Interdependence Between Methylation and Disease Pathogenesis: A Genome-Wide Methylation Analysis

“…NRG1 is a member of the neuregulin family that interacts with the EGFR family and modulates the repair of neural damage as well as immune response in the nervous system ( Kataria et al, 2019 ). Apart from neural modulatory function, secretion of NRG1 from fibroblast and endothelial cells also participates in the fibrotic remodeling of myocardial cells ( Dugaucquier et al, 2020 ). Whole-genome sequence analysis has revealed the association between NRG1 and free thyroxine ( Taylor et al, 2015 ), while it has also been found to influence the predisposition to thyroid carcinoma ( He et al, 2018 ).…”

Neuregulin-1, a potential therapeutic target for cardiac repair

“…NRG1 ligand binding triggers homodimerization of ErbB4 and heterodimerization of ErbB2/3, ErbB2/4, ErbB3/4 ( Carraway and Cantley, 1994 ; Sweeney et al, 2001 ; Yarden and Sliwkowski, 2001 ), followed by downstream signaling through the central pathway ( Xu et al, 2010 ; Fernandez-Cuesta et al, 2014 ). In some studies, the NRG1-ErbB pathway is believed to be a compensatory protective mechanism for cardiac injury ( Bersell et al, 2009 ; Odiete et al, 2012 ; Dugaucquier et al, 2020 ). The NRG1-ErbB signaling axis is a critical mediator of cardiac development, and growing evidence supports a role for this system in the intricate cross-talk between the microvascular endothelium and myocytes in the adult heart.…”

Identification of inflammation-related DNA methylation biomarkers in periodontitis patients based on weighted co-expression analysis

“…NRG1, which controls the formation of excitatory and inhibitory synapses in cortical circuits, is a schizophrenia risk gene [39], and is associated with multiple relapsing disorders. In addition, NRG1 plays an important role in parabens of fibroblasts and macrophages [40]. Overexpression of mutant PMP2 also leads to CMT1 phenotype [41], and aberrant AKT3 expression helps form M2 macrophage specificity [42].…”