Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy

Zhan Peng Huang, Yan Ding, Jinghai Chen, Gengze Wu, Masaharu Kataoka, Yongwu Hu, Jian Hua Yang, Jianming Liu, Stavros G. Drakos, Craig H. Selzman, Jan Kyselovic, Liang Hu Qu, Cristobal G. Dos Remedios, William T. Pu, Da Zhi Wang

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Aims Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts. Methods and results In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n = 15) and controls (n = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-β pathway to modulate the expression of ECM genes and myofibroblast differentiation. Conclusion Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.

Original languageEnglish
Pages (from-to)543-554
Number of pages12
JournalCardiovascular Research
Volume112
Issue number2
DOIs
Publication statusPublished - 2016 Nov 1

Fingerprint

Long Noncoding RNA
Cardiomyopathies
Extracellular Matrix
Gene Expression
Heart Failure
Genes
Fibrosis
RNA Sequence Analysis
Biological Phenomena
High-Throughput Nucleotide Sequencing
Untranslated RNA
Myofibroblasts
Extracellular Matrix Proteins
Gene Expression Profiling

Keywords

  • Extracellular matrix
  • Heart disease
  • Ischemic cardiomyopathy
  • lncRNA
  • Non-coding RNAs

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Huang, Z. P., Ding, Y., Chen, J., Wu, G., Kataoka, M., Hu, Y., ... Wang, D. Z. (2016). Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. Cardiovascular Research, 112(2), 543-554. https://doi.org/10.1093/cvr/cvw201

Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. / Huang, Zhan Peng; Ding, Yan; Chen, Jinghai; Wu, Gengze; Kataoka, Masaharu; Hu, Yongwu; Yang, Jian Hua; Liu, Jianming; Drakos, Stavros G.; Selzman, Craig H.; Kyselovic, Jan; Qu, Liang Hu; Dos Remedios, Cristobal G.; Pu, William T.; Wang, Da Zhi.

In: Cardiovascular Research, Vol. 112, No. 2, 01.11.2016, p. 543-554.

Research output: Contribution to journalArticle

Huang, ZP, Ding, Y, Chen, J, Wu, G, Kataoka, M, Hu, Y, Yang, JH, Liu, J, Drakos, SG, Selzman, CH, Kyselovic, J, Qu, LH, Dos Remedios, CG, Pu, WT & Wang, DZ 2016, 'Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy', Cardiovascular Research, vol. 112, no. 2, pp. 543-554. https://doi.org/10.1093/cvr/cvw201
Huang, Zhan Peng ; Ding, Yan ; Chen, Jinghai ; Wu, Gengze ; Kataoka, Masaharu ; Hu, Yongwu ; Yang, Jian Hua ; Liu, Jianming ; Drakos, Stavros G. ; Selzman, Craig H. ; Kyselovic, Jan ; Qu, Liang Hu ; Dos Remedios, Cristobal G. ; Pu, William T. ; Wang, Da Zhi. / Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. In: Cardiovascular Research. 2016 ; Vol. 112, No. 2. pp. 543-554.
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abstract = "Aims Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts. Methods and results In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n = 15) and controls (n = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-β pathway to modulate the expression of ECM genes and myofibroblast differentiation. Conclusion Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.",
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AU - Huang, Zhan Peng

AU - Ding, Yan

AU - Chen, Jinghai

AU - Wu, Gengze

AU - Kataoka, Masaharu

AU - Hu, Yongwu

AU - Yang, Jian Hua

AU - Liu, Jianming

AU - Drakos, Stavros G.

AU - Selzman, Craig H.

AU - Kyselovic, Jan

AU - Qu, Liang Hu

AU - Dos Remedios, Cristobal G.

AU - Pu, William T.

AU - Wang, Da Zhi

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Aims Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts. Methods and results In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n = 15) and controls (n = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-β pathway to modulate the expression of ECM genes and myofibroblast differentiation. Conclusion Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.

AB - Aims Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts. Methods and results In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n = 15) and controls (n = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-β pathway to modulate the expression of ECM genes and myofibroblast differentiation. Conclusion Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.

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KW - lncRNA

KW - Non-coding RNAs

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