Increased Cardiac Arrhythmogenesis Associated With Gap Junction Remodeling With Upregulation of RNA-Binding Protein FXR1

Abstract

In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1, namely, that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart.

CELF1 regulates gap junction integrity contributing to dilated cardiomyopathy

“…Specifically, dilated cardiomyopathy (DCM) is a prominent cause of heart failure, heart transplantation, and death (1–4,7–12). DCM is described as dilation of the left ventricle as well as impaired systolic function with a reduced ejection fraction (2,11).…”

“…Cell-to-cell communication is important for healthy heart function, and importantly, disruptions to this necessary coupling event can lead to ventricular arrhythmias (6,7,9,13). This connection processes occur through intercalated discs within the cardiac muscle, and consist of three complexes including gap junctions, fascia adherins, and desmosomes (7).…”

“…This connection processes occur through intercalated discs within the cardiac muscle, and consist of three complexes including gap junctions, fascia adherins, and desmosomes (7). Changes to these cell-to-cell connections at intercalated discs can lead to DCM (7). Gap junctions are at the center of these events and allow for proper electrical coupling (8,9,13,14).…”

“…Connexin 40 (Cx40), connexin 45 (Cx45), and connexin 43 (Cx43) are the three main gap junction proteins found in the heart (5). Cx43 is the most common connexin (5–7,13–16) and is expressed in over 46 different cell types, but most predominantly in the heart (14). Cx43 is typically located at intercalated discs of cardiomyocytes (13) and is predominantly expressed between the ventricular and atrial myocytes (5).…”

“…DCM patients for example, display significantly decreased Cx43 expression levels (6–9), while it is thought that an increase in Cx43 expression is a part of the adaptive cardiac pathologic remodeling phase (6). Alterations in cell-cell communications at intercalated discs can disrupt chemical exchanges and electrical coupling, and is known as gap junction remodeling (7). Recent work by Chang et al demonstrated that CELF1 is involved in the degradation of Cx43 mRNA and suggested a role for CELF1 in DCM (6).…”