Browsing by Author "Wang, Yi-Zhen"

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Idi1 and Hmgcs2 Are Affected by Stretch in HL-1 Atrial Myocytes
(2018-12-01)
Fang, Chih-Yuan
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Chen, Mien-Cheng
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Chang, Tzu-Hao
;
Wu, Chia-Chen
;
Chang, Jen-Ping
Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). Results: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the superpathway of cholesterol biosynthesis were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). Conclusions: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.
Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing-Induced Cardiomyopathy
(2019-01-08)
Lin, Yu-Sheng
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Chang, Tzu-Hao
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Shi, Chung-Sheng
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Wang, Yi-Zhen
;
Ho, Wan-Chun
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.