Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy
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 betwe...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.118.009146 |
| _version_ | 1819175112518139904 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yu‐Sheng Lin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T20:49:41Z |
| format | Article |
| id | doaj.art-c47cfc4e73094b71b64bf838f57911cc |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-22T20:49:41Z |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-c47cfc4e73094b71b64bf838f57911cc2022-12-21T18:13:07ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802019-01-018110.1161/JAHA.118.009146Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced CardiomyopathyYu‐Sheng Lin0Tzu‐Hao Chang1Chung‐Sheng Shi2Yi‐Zhen Wang3Wan‐Chun Ho4Hsien‐Da Huang5Shih‐Tai Chang6Kuo‐Li Pan7Mien‐Cheng Chen8Division of Cardiology Chang Gung Memorial Hospital Chiayi TaiwanGraduate Institute of Biomedical Informatics Taipei Medical University Taipei TaiwanGraduate Institute of Clinical Medical Sciences College of Medicine Chang Gung University Taoyuan TaiwanDivision of Cardiology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine Kaohsiung TaiwanDivision of Cardiology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine Kaohsiung TaiwanThe Warshel Institute of Computational Biology School of Science and Technology The Chinese University of Hong Kong Shenzhen ChinaDivision of Cardiology Chang Gung Memorial Hospital Chiayi TaiwanDivision of Cardiology Chang Gung Memorial Hospital Chiayi TaiwanDivision of Cardiology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine Kaohsiung TaiwanBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.118.009146atrioventricular blockcardiomyopathyliver X receptor/retinoid X receptor pathwaypacing |
| spellingShingle | 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 Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atrioventricular block cardiomyopathy liver X receptor/retinoid X receptor pathway pacing |
| title | Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy |
| title_full | Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy |
| title_fullStr | Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy |
| title_full_unstemmed | Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy |
| title_short | Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing‐Induced Cardiomyopathy |
| title_sort | liver x receptor retinoid x receptor pathway plays a regulatory role in pacing induced cardiomyopathy |
| topic | atrioventricular block cardiomyopathy liver X receptor/retinoid X receptor pathway pacing |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.118.009146 |
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