Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy

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 ( DEG s) 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 DEG s ( ABCA 1, APOD , CLU , LY 96, and SERPINF 1) in the LV septum (z‐score=−0.447) and 5 DEG s ( APOD , CLU , LY 96, MSR 1, and SERPINF 1) in the LV free wall (z‐score=−1.000) inhibited the liver X receptor/retinoid X receptor ( LXR / RXR ) pathway, and 4 DEG s ( ACTA 2, MYL 1, PPP 2R3A, and SNAI 2) 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 DEG s 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.

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

“…A more recent study revealed upregulation of the LXR-RXR pathway in samples of human hypertrophic cardiomyopathy, suggesting that LXRs also play an important role in cardiac disease in humans [201]; however, whether this effect contributes to cardioprotection is unknown. Strikingly, a pig model of pacing-induced cardiomyopathy revealed inhibition of the LXR-transcriptional pathway accompanied by increased hypertrophy and fibrosis [202]. This result hints at a complex upstream regulation of LXRs, which may be different in the context of pacing-induced cardiomyopathy.…”

Role of cellular retinol‐binding protein, type 1 and retinoid homeostasis in the adult mouse heart: A multi‐omic approach

“…Systemic LXR/RXR activation is also important for providing myocardial protection against many diseases, including atherosclerosis, hypertension, and diabetes 77 . Recently, several studies have established that dysregulated LXR/RXR activation was associated with heart disease 78–80 . LXR is activated by oxysterols and there were no oxysterols on our metabolomic panel.…”

“…77 Recently, several studies have established that dysregulated LXR/RXR activation was associated with heart disease. [78][79][80] LXR is activated by oxysterols and there were no oxysterols on our metabolomic panel. In this study, proteins related to the LXR/RXR activation pathway had altered levels in Rbp1 -/mice compared to WT mice, in both the left and right ventricles (Table 3).…”

Reorganization of Metabolism during Cardiomyogenesis Implies Time-Specific Signaling Pathway Regulation

“…The role of PPARα-RXR in regulating the expression of genes related to lipid and energy metabolism in cardiac tissue is well reported in the literature in both cardiac physiology and in pathological conditions (reviewed in [ 26 , 27 ]). On the other hand, the influence of LXR and FXR on cardiac signaling, metabolism and development is not well understood, although studies have related these pathways to cardiovascular pathologies [ 23 , 28 , 29 , 30 , 31 ].…”