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

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-02, Vol.137 (6), p.605-618
• Main Authors: Chu, Miensheng, Novak, Stefanie Mares, Cover, Cathleen, Wang, Anne A, Chinyere, Ikeotunye Royal, Juneman, Elizabeth B, Zarnescu, Daniela C, Wong, Pak Kin, Gregorio, Carol C
• Format: Article
• Language: English
• Subjects: Animals; Cardiomyopathy, Hypertrophic - complications; Cardiomyopathy, Hypertrophic - metabolism; Cardiomyopathy, Hypertrophic - pathology; Cardiomyopathy, Hypertrophic - physiopathology; Cell Communication; Connexins - genetics; Connexins - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Disease Models, Animal; Gap Junctions - metabolism; Gap Junctions - pathology; Heart Ventricles - metabolism; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Humans; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins - genetics; Muscle Proteins - metabolism; Rats; Risk Factors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; Tachycardia, Ventricular - etiology; Tachycardia, Ventricular - metabolism; Tachycardia, Ventricular - pathology; Tachycardia, Ventricular - physiopathology; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling; Zonula Occludens-1 Protein - genetics; Zonula Occludens-1 Protein - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.117.028976

BACKGROUND—Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and post-transcriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of Fragile X mental retardation autosomal homolog 1 (FXR1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear. METHODS—To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identifythe functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates it targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus. RESULTS—FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via western blot analysis. FXR1 associates with intercalated discs and integral gap junction proteins Cx43, Cx45 and ZO-1 were identified as novel mRNA targets of FXR1 using a BioID proximity assay and RNA immunoprecipitation. Our findings show FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. Additionally, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to redistribution of gap junctions and promotes ventricular tachycardia showing functional significance of FXR1 upregulation observed in DCM. CONCLUSIONS—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.