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

Abstract

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.

• Authors: Hsiang-Chun Lee, Chih-Chieh Chen, Wei-Chung Tsai, Hsin-Ting Lin, Yi-Lin Shiao, Sheng-Hsiung Sheu, Bin-Nan Wu, Chu-Huang Chen, Wen-Ter Lai
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 12050 (09 21 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28935953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Connexin 43
• Connexins
• Lipoproteins, VLDL

Topics

• Animals
• Cell Line
• Connexin 43 (chemistry, genetics, metabolism)
• Connexins (chemistry, genetics, metabolism)
• Electrocardiography
• Gap Junctions (drug effects, physiology)
• Gene Expression (drug effects)
• Glycosylation (drug effects)
• Heart (drug effects, physiopathology)
• Heart Conduction System (drug effects, physiopathology)
• Humans
• Lipoproteins, VLDL (administration & dosage, pharmacology)
• Male
• Metabolic Syndrome (metabolism, physiopathology)
• Mice, Inbred C57BL
• Myocardium (cytology, metabolism)
• Gap Junction alpha-5 Protein