Very-Low-Density Lipoprotein of Metabolic Syndrome Modulates Gap Junctions and Slows Cardiac Conduction

• Published in: Scientific reports Vol. 7; no. 1; pp. 12050 - 12
• Main Authors: Lee, Hsiang-Chun, Chen, Chih-Chieh, Tsai, Wei-Chung, Lin, Hsin-Ting, Shiao, Yi-Lin, Sheu, Sheng-Hsiung, Wu, Bin-Nan, Chen, Chu-Huang, Lai, Wen-Ter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-09-2017; Nature Publishing Group
• Subjects: 13/51; 14/19; 631/114/2411; 64/60; 692/4019/592/75/29/1309; Animals; Cardiac arrhythmia; Cell Line; Conduction; Connexin 43; Connexin 43 - chemistry; Connexin 43 - genetics; Connexin 43 - metabolism; Connexins - chemistry; Connexins - genetics; Connexins - metabolism; Cytotoxicity; Electrocardiography; Fibrillation; Fibrosis; Gap Junction alpha-5 Protein; Gap junctions; Gap Junctions - drug effects; Gap Junctions - physiology; Gene Expression - drug effects; Glycosylation - drug effects; Heart - drug effects; Heart - physiopathology; Heart Conduction System - drug effects; Heart Conduction System - physiopathology; Heart diseases; Humanities and Social Sciences; Humans; Lipoproteins; Lipoproteins (very low density); Lipoproteins, VLDL - administration & dosage; Lipoproteins, VLDL - pharmacology; Low density lipoprotein; Lymphocytes T; Male; Metabolic syndrome; Metabolic Syndrome - metabolism; Metabolic Syndrome - physiopathology; Mice, Inbred C57BL; multidisciplinary; Myocardium - cytology; Myocardium - metabolism; O-GlcNAcylation; Protein structure; Science; Science (multidisciplinary); Serine; Transcription; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-11416-5

Very-low-density lipoproteins (VLDL) is a hallmark of metabolic syndrome (MetS) and each manifestation of MetS is related to atrial fibrillation (AF) risks. Slowed atrial conduction is a mechanism of AF in MetS. We hypothesized that VLDL can modulate and reduce atrial gap junctions. VLDLs were separated from normal (Normal-VLDL) and MetS (MetS-VLDL) individuals. VLDLs (15 µg/g) and equivalent volumes of saline (CTL) were injected respectively to C57BL/6 mice for 6 weeks. Electrocardiograms demonstrated that MetS-VLDL induced prolongation of P wave (P = 0.041), PR intervals (P = 0.014), QRS duration and QTc interval (both P = 0.003), but Normal-VLDL did not. Optical mapping of perfused hearts confirmed slowed conduction on atria and ventricles of MetS-VLDL mice. Slowed cardiac conduction was associated with significant atrial and ventricular remodeling, along with systolic dysfunction and comparable intra-cardiac fibrosis. MetS-VLDL induced downregulation of Cx40 and Cx43 at transcriptional, translational and tissue levels, and it also enhanced O-GlcNAcylation of Cx40 and Cx43. Protein structure analyses predicted O-GlcNAcylation at serine 18 of Cx40 and Cx43 which may impair stability of gap junctions. In conclusion, MetS-VLDL modulates gap junctions and delays both atrial and ventricular conduction. VLDL may contribute to the pathophysiology of atrial fibrillation and ventricular arrhythmias in MetS.