Liver X receptor/retinoid X receptor pathway plays a regulatory role in pacing-induced cardiomyopathy

Yu Sheng Lin, Tzu Hao Chang, Chung Sheng Shi, Yi Zhen Wang, Wan Chun Ho, Hsien Da Huang, Shih Tai Chang, Kuo Li Pan, Mien Cheng Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

14 Scopus citations

Abstract

Background-—The molecular mechanisms through which high-demand pacing induce myocardial dysfunction remain unclear. Methods and Results-—We created atrioventricular block in pigs using dependent right ventricular septal pacing for 6 months. Echocardiography was performed to evaluate dyssynchrony between pacing (n=6) and sham control (n=6) groups. Microarray and enrichment analyses were used to identify differentially expressed genes (DEGs) in the left ventricular (LV) myocardium between pacing and sham control groups. Histopathological and protein changes were also analyzed and an A cell pacing model was also performed. Pacing significantly increased mechanical dyssynchrony. Enrichment analysis using Ingenuity Pathway Analysis and the activation z-score analysis method demonstrated that there were 5 DEGs (ABCA1, APOD, CLU, LY96, and SERPINF1) in the LV septum (z-score= 0.447) and 5 DEGs (APOD, CLU, LY96, MSR1, and SERPINF1) in the LV free wall (z-score= 1.000) inhibited the liver X receptor/retinoid X receptor (LXR/RXR) pathway, and 4 DEGs (ACTA2, MYL1, PPP2R3A, and SNAI2) activated the integrin-linked kinase (ILK) pathway in the LV septum (z-score=1.000). The pacing group had a larger cell size, higher degree of myolysis and fibrosis, and increased expression of intracellular lipid, inflammatory cytokines, and apoptotic markers than the sham control group. The causal relationships between pacing and DEGs related to LXR/RXR and ILK pathways, apoptosis, fibrosis, and lipid expression after pacing were confirmed in the cell pacing model. Luciferase reporter assay in the cell pacing model also supported inhibition of the LXR pathway by pacing. Conclusions-—Right ventricular septal-dependent pacing was associated with persistent LV dyssynchrony–induced cardiomyopathy through inhibition of the LXR/RXR pathway.

Original languageEnglish
Article numbere009146
JournalJournal of the American Heart Association
Volume8
Issue number1
DOIs
StatePublished - 01 01 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors.

Keywords

  • Atrioventricular block
  • Cardiomyopathy
  • Liver X receptor/retinoid X receptor pathway
  • Pacing

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