MicroRNAs in Heart Failure: Non-coding Regulators of Metabolic Function Xiaokan Zhang, P. Christian Schulze PII: DOI: Reference:
S0925-4439(16)30198-3 doi: 10.1016/j.bbadis.2016.08.009 BBADIS 64534
To appear in:
BBA - Molecular Basis of Disease
Received date: Revised date: Accepted date:
25 May 2016 10 August 2016 11 August 2016
Please cite this article as: Xiaokan Zhang, P. Christian Schulze, MicroRNAs in Heart Failure: Non-coding Regulators of Metabolic Function, BBA - Molecular Basis of Disease (2016), doi: 10.1016/j.bbadis.2016.08.009
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ACCEPTED MANUSCRIPT MicroRNAs in Heart Failure: Non-coding Regulators of Metabolic Function
Xiaokan Zhang1 and P. Christian Schulze1, 2 1
Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY,
Department of Medicine I, Division of Cardiology, Angiology, Pneumology and Intensive Medical Care,
Friedrich-Schiller-University Jena, Jena, Germany;
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P. Christian Schulze, Department of Medicine I, Division of Cardiology, Angiology, Pneumology and Intensive Medical Care, Friedrich-Schiller-University Jena, University Hospital Jena, 07743 Jena, Germany, Tel.: ++49-3641-932-4101; Fax: ++49-3641-9324103; E-mail: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT Heart failure (HF) is the inability of the heart to provide sufficient cardiac output for the energy
demands of the body. Over the last decades, our understanding of the role of microRNAs (miRNAs), a class of small non-coding RNA regulators of gene expression at the post-
transcriptional level, in cardiovascular diseases has expanded at a rapid rate. Importantly,
multiple miRNAs have been specifically implicated in the progression of HF. Growing evidence suggests that miRNAs regulate central metabolic pathways and thus are highly implicated in the
maintenance of energy homeostasis. In this review, we highlight recent discoveries of the
mechanistic role of miRNAs in regulating metabolic functions in HF, with specific focus on the implication of miRNAs in metabolic rearrangements, discuss the potential value of miRNA
profiles as novel HF biomarkers, and summarize the recent investigations on therapeutic
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approaches using miRNAs in heart disease.
Key Words: Heart failure, micro RNA, metabolism
ACCEPTED MANUSCRIPT Heart failure (HF) is a disease of increasing incidence and prevalence with high morbidity and mortality. It includes derangements in metabolic pathways and disturbed energy homeostasis.
MicroRNAs (miRNAs) are highly expressed in the heart and the significance of miRNAs in cardiac development, physiology and disease was elucidated over the last years through
various key studies. Cardiac-specific deletion of the miRNA biogenesis key enzyme Dicer in
mice has been shown to result in embryonic lethality due to HF . In the past decades, miRNAs have been increasingly described to regulate a diverse spectrum of processes in the
heart, and are a vital part of normal cardiac function and cardiac development. Interestingly, a
growing body of evidence indicates that miRNAs are implicated as sensors of environmental changes in the settings of heart disease and HF, suggesting their up- or downregulation plays either a causative or protective role by modulating key signaling elements and enzymes in the
metabolic pathways. The diagnostic roles of miRNAs in the assessment of heart disease and the modulation of miRNAs as a new therapeutic option have been widely explored, and new
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findings are continuously emerging. In the present review, we summarize the dysregulation of miRNAs, their role as biomarkers in the failing myocardium, highlight the role of miRNAmediated metabolic regulation in the cardiac function and discuss the strategy of targeting miRNAs for cardiac disease therapy.
ROLE OF miRNAs IN REGULATING GENE EXPRESSION miRNAs are small single-stranded non-coding RNAs (approximately 22 nucleotides in length), and their best characterized function is to regulate gene expression at the post-transcriptional level . Indeed, most mammalian protein coding genes are under the control of miRNAs via their near-perfect base-pairing with the 3’UTR of the target mRNAs through their 5'-proximal “seeding” region [3, 4].
ACCEPTED MANUSCRIPT miRNAs are encoded within the genomes of species ranging from protozoans to plants to mammals. miRNAs are first transcribed by RNA polymerase II enzyme into long (~1000
nucleotides in length) precursor molecules called primary miRNAs (pri-miRNAs), and are further transformed into smaller (