Browsing by Author "Pan, Kuo-Li"

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Circulating miR-148b-3p and miR-409-3p as biomarkers for heart failure in patients with mitral regurgitation
(2016-11-01)
Chen, Mien-Cheng
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Chang, Tzu-Hao
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Chang, Jen-Ping
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Huang, Hsien-Da
;
Ho, Wan-Chun
Background: MicroRNAs (miRs) regulate gene expression in heart failure. Circulating miRs as biomarkers for heart failure in mitral regurgitation patients (MR) remain unexplored. Methods: This case-control study enrolled 32 MR patients with heart failure, 16 asymptomatic MR patients, and 12 control subjects without heart failure. We used next generation sequencing to study the gene expression profiles in the sera, and quantitative RT-PCR to study serum and tissue miRs in the left atria. Results: Next generation sequencing analysis and enrichment analysis showed that 25 miRs were differentially expressed in the sera of MR patients with heart failure compared to control subjects. The circulating miR-148b-3p (p = 0.002) and miR-409-3p (p = 0.010) were significantly down-regulated in the MR patients with heart failure compared to control subjects. However, only circulation miR-148b-3p was significantly down-regulated in the MR patients without heart failure compared to control subjects (p = 0.009). The tissue miR-409-3p was significantly down-regulated in the MR patients with heart failure compared to 3 purchased normal controls (p = 0.041). Notably, the tissue RASGRP3 mRNA, target gene of miR-409-3p, was significantly upregulated in the MR patients with heart failure compared to normal controls (p = 0.010). The tissue FRY (p = 0.010) and GADD45A (p = 0.010) mRNAs, target genes of miR-148b-3p, were significantly up-regulated in the MR patients with heart failure compared to normal controls. Conclusions: Circulating miR-148b-3p might serve as biomarker for future development of heart failure and miR-409-3p might serve as biomarker for incident heart failure in MR patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Exploring Regulatory Mechanisms of Atrial Myocyte Hypertrophy of Mitral Regurgitation through Gene Expression Profiling Analysis: Role of NFAT in Cardiac Hypertrophy
(2016-12-01)
Chang, Tzu-Hao
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Chen, Mien-Cheng
;
Chang, Jen-Ping
;
Huang, Hsien-Da
;
Ho, Wan-Chun
Background Left atrial enlargement in mitral regurgitation (MR) predicts a poor prognosis. The regulatory mechanisms of atrial myocyte hypertrophy of MR patients remain unknown. Methods and Results This study comprised 14 patients with MR, 7 patients with aortic valve disease (AVD), and 6 purchased samples from normal subjects (NC). We used microarrays, enrichment analysis and quantitative RT-PCR to study the gene expression profiles in the left atria. Microarray results showed that 112 genes were differentially up-regulated and 132 genes were differentially down-regulated in the left atria between MR patients and NC. Enrichment analysis of differentially expressed genes demonstrated that "NFAT in cardiac hypertrophy" pathway was not only one of the significant associated canonical pathways, but also the only one predicted with a non-zero score of 1.34 (i.e. activated) through Ingenuity Pathway Analysis molecule activity predictor. Ingenuity Pathway Analysis Global Molecular Network analysis exhibited that the highest score network also showed high association with cardiac related pathways and functions. Therefore, 5 NFAT associated genes (PPP3R1, PPP3CB, CAMK1, MEF2C, PLCE1) were studies for validation. The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in MR patients compared to NC. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to AVD patients. The atrial myocyte size of MR patients significantly exceeded that of the AVD patients and NC. Conclusions Differentially expressed genes in the "NFAT in cardiac hypertrophy" pathway may play a critical role in the atrial myocyte hypertrophy of MR patients.
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
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Wu, Chia-Chen
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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
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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.