Nature Reviews Cardiology
During stress or injury-induced cardiac remodelling, fibroblasts increase production of extracellular matrix proteins, which leads to fibrosis formation, and consequently, heart failure. In this Review, Thomas Thum describes the contribution of noncoding RNAs to this process, with a specific focus on microRNAs that might be used as future therapeutic targets or biomarkers for cardiac fibrosis.
Abstract:
Cardiac stress leads to remodelling of cardiac tissue, which often progresses to heart failure and death. Part of the remodelling process is the formation of fibrotic tissue, which is caused by exaggerated activity of cardiac fibroblasts leading to excessive extracellular matrix production within the myocardium. Noncoding RNAs (ncRNAs) are a diverse group of endogenous RNA-based molecules, which include short (~22 nucleotides) microRNAs and long ncRNAs (of >200 nucleotides). These ncRNAs can regulate important functions in many cardiovascular cells types. This Review focuses on the role of ncRNAs in cardiac fibrosis; specifically, ncRNAs as therapeutic targets, factors for direct fibroblast transdifferentation, their use as diagnostic and prognostic markers, and their potential to function as paracrine modulators of cardiac fibrosis and remodelling.
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| Figure 1: ncRNAs in fibroblast biology.
miRNAs and lncRNAs are important intracellular regulators of gene expression, but also directly or indirectly regulate proteins. pri-miRNAs are processed by Drosha into pre-miRNAs, before the endonuclease Dicer generates a mature miRNA. ncRNAs serve as therapeutic targets, but are also secreted from fibroblasts and are potential diagnostic markers and paracrine signalling mediators between cells. miRNAs and lncRNAs are likely to be involved in differentitation and transdifferentiation processes, such as direct transdifferentiation of fibroblasts towards a cardiomyocyte fate. Abbreviations: lncRNA, long noncoding RNA; miRNA, microRNA; ncRNA, noncoding RNA.
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| Figure 2: ncRNAs in transdifferentiation of fibroblasts towards cardiomyocytes.
A combination of different factors, such as GATA-4, TBX5, and MEF2C, can initiate transdifferentiation, although these events are rare. Addition of miRNAs and possibly lncRNAs are likely to support this process. In the future, these factors might form therapeutic approaches to enable fibrotic scarring in the heart to redifferentiate into healthy functional myocardium. Whether cardiomyocytes can dedifferentiate back into fibroblasts is currently unknown. Abbreviations: GATA-4, transcription factor GATA-4; HAND2, heart and neural crest derivatives-expressed protein 2; JAK1, tyrosine-protein kinase JAK1; lncRNA, long noncoding RNA; MEF2C, myocyte-specific enhancer factor 2C; miRNA, microRNA; ncRNA, noncoding RNA; TBX5, T-box transcription factor TBX5.
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| Figure 3: Cardiac fibroblasts involved in intercellular communication.
Cardiac fibroblasts communicate with multiple cell types within the myocardium, such as cardiomyocytes, with endothelial and immune cells by secretion of cytokines and growth factors, and by exchanging genetic material such as miRNAs via vesicles. The communication is not unidirectional and nonfibroblast cells communicate with cardiac fibroblasts via cytokines, growth factors (such as FGF2 and CTGF), probably via vesicles, and also by direct cell–cell communication. Abbreviations: CTGF, connective tissue growth factor; FGF2, fibroblast growth factor 2; lncRNA, long noncoding RNA; miRNA, microRNA; ncRNA, noncoding RNA.
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