ABC | Volume 111, Nº5, November 2018

Review Article Role of miRNAs on the Pathophysiology of Cardiovascular Diseases Debora Cristina Pereira da Silva, 1 Felipe Demani Carneiro, 1 Kelly Costa de Almeida, 2 Caroline Fernandes-Santos 1 Programa de Pós-graduação em Ciências Cardiovasculares da Universidade Federal Fluminense (UFF), 1 Niterói, RJ – Brazil Universidade Federal Fluminense (UFF), 2 Nova Friburgo, RJ – Brazil Keywords Cardiovascular Diseases/physiopathology; Cardiovascular Diseases/diagnosis; Cardiovascular Diseases/genetics; Biomarkers/metabolism; Cardiac, Remodeling/genetics; Atherosclerosis; MicroRNAs. Mailing Address: Caroline Fernandes dos Santos Bottino • Rua Dr Silvio Henrique Braune, 22. Postal Code 28625-650, Centro, Nova Friburgo, RJ - Brazil E-mail: cf_santos@id.uff.br Manuscript received August 19, 2017, revised manuscript October 21, 2017, accepted October 25, 2017 DOI: 10.5935/abc.20180215 Abstract MiRNA (or microRNA) is a subclass of non-coding RNAs that is responsible for post-transcriptional gene regulation. It has approximately 22 nucleotides and regulates gene expression in plants and animals at the post-transcriptional level, by the cleavage of a target mRNA or by suppression of its translation. Although many of the processes and mechanisms have not yet been fully elucidated, there is a strong association between miRNA expression and several diseases. It is known that miRNAs are expressed in the cardiovascular system, but their role in cardiovascular diseases (CVDs) has not been clearly established. In this non-systematic review of the literature, we first present the definition of miRNAs and their action at the cellular level. Afterward, we discuss the role of miRNAs as circulating biomarkers of CVDs, and then their role in cardiac remodeling and atherosclerosis. Despite the complexity and challenges, it is crucial to identify deregulated miRNAs in CVDs, as it allows a better understanding of underlying cellular and molecular mechanisms and helps in the development of more accurate diagnostic and prognostic circulating biomarkers, and new therapeutic strategies for different stages of CVDs. Introduction Scientific research has been done in attempts to explain the pathophysiology of several diseases for the development of new therapies. In this regard, miRNA (or microRNA) has drawn attention of scientific community as a potential therapeutic target. Since their discovery in 1993, 1 several miRNAs related to biologic processes for their gene-regulatory roles have been cataloged. However, many miRNAs remain to be discovered, which makes them one of the largest classes of gene regulators. To give an idea of the importance of miRNAs, these molecules regulate approximately one third of all gene expression in mammals. 2 Although many studies have successfully established an association between miRNA expression patterns and several diseases, many mechanisms and processes involved have not been fully elucidated. In diabetes mellitus, for example, results of experimental studies have indicated that specific miRNAs present in pancreatic islets may play a regulatory role in insulin secretion. 3 MiRNA expression may also be visualized in different types of tumors, acting either as tumor suppressors or exerting an opposite role with deleterious effects. 4 Although it is currently known that miRNAs are expressed in the cardiovascular system, their role on the development of cardiovascular diseases (CVDs) still need to be better understood. In light of this, we conducted a systematic review aimed at summarizing and discussing the findings of the main studies investigating the relationship between miRNAs and CVD. We searched for articles published in the PubMed database (www.ncbi.nlm.nih.gov/pubmed) . Original articles written in English, involving humans or animals, were selected using the following MeSH terms – microRNA AND Cardiovascular Diseases, miRNA AND Cardiovascular Diseases. In this review, we first describe the definition of miRNAs and their actions at the cellular level. Subsequently, we discuss the role of miRNAs as circulating biomarkers, and their role in cardiac remodeling and atherosclerosis. MiRNA biology For many years, it was believed that non-coding regions of the genome were “junk”, as they did not carry information for protein synthesis. Currently, it is known that most of the eukaryotic transcriptome is composed by noncoding RNAs, which are classified as functional and regulators. Among functional RNAs, there are transfer RNA (tRNA), small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA); major classes of RNAs regulators aremiRNAs, small interfering RNAs (siRNAs), piwiRNAs (piRNAs) and long noncoding RNAs (lncRNAs). 5 Among this wide variety of noncoding RNA classes, much attention has been drawn to miRNAs because of the association between dysregulation of these molecules and development of phenotypic and pathological changes. 6 MiRNAs are defined as single-stranded, small noncoding RNA molecules containing about 22 nucleotides (nt). They function in post-transcriptional regulation of gene expression in plants and animals by means of cleavage of the target messenger RNA (mRNA) or by suppression of mRNA translation. 7 The first miRNA, lin-4, was described in 1993 by the group of Rosalind Lee as a miRNA involved in the larval development of Caenorhabditis elegans ( C. elegans ). Lin-4 negatively regulates the level of LIN-14 protein in the first larval stage, decreasing its expression over time. 1 MiRNA biogenesis starts with the synthesis of a long primary transcript, known as pri-miRNA (~110pb) (Figure 1). Pri-miRNAs are transcribed by RNA polymerase II or III; 8 738