ABC | Volume 111, Nº5, November 2018

Review Article Silva et al miRNAs and cardiovascular disease Arq Bras Cardiol. 2018; 111(5):738-746 Progression of fatty streaks to fibrous cap of an atheroma is mainly caused by proliferation andmigration of vascular smooth muscle cells (VSMCs) to the intima. Proliferation and apoptosis of these cells are regulated by TGF- β , which, in turn, is negatively regulated by miR-26a (i.e., miR-26 inhibition promotes VSMC differentiation) in human serum. 67 In addition, both miR-21 and miR-221 also modulate the proliferation of VSMC; miR‑221 acts in response to platelet derived growth factor (PDGF). Also, miR-221 negatively regulates p2Kip1, which is critical for induction of cell proliferation mediated by PDGF, whereas c-Kit may be associated with inhibition of VSMC-specific contractile gene transcription by reducing the expression of myocardin, a potent VSMC-specific nuclear coactivator. 68 Neoangionesis During the development of atherosclerotic plaque, activated, cholesterol-containing macrophages are responsible for the release of several cytokines, including those involved in neoangiogenesis. MiRNAs involved in this process include miR-221, -222, -155, -27a, -27b and -210. In HUVEC cells, miR-222/221 affect the expression of c-Kit, 69 and miR-222 is involved in vascular remodeling mediated by inflammation. 70 MiR-155 seems to regulate the expression of endothelial nitric oxide synthase (eNOS) and endothelium-dependent vascular relaxation. 71 In a three-dimensional spheroid model, increased expression of miR-27a/b stimulates endothelial cell sprouting, indicating its pro-angiogenic effect, since they target semaphorin 6A, an angiogenesis inhibitor. 72 Finally, miR-210 expression in HUVEC progressively increases in hypoxia and its increased expression in normoxia leads to formation of capillary-like structures by VEGF on Matrigel. 73 Plaque instability and rupture Instability and rupture of the fibrous capsule of an atherosclerotic plaque depend on the balance between synthesis and degradation of the ECM by fibroblasts. Plaque rupture is the main mechanism involved in the development of stroke and AMI, and sudden death. Matrix metalloproteinases (MMPs) act in collagen degradation, especiallyMMP-1, MMP-2, MMP-3 and MMP-9 released by activated macrophages. 74 MMP-9 is regulated by miR-133a/b, which can also modulate VSMC apoptosis and proliferation in animal models. 75 Cipollone et al. 76 investigated miRNA expression and its correlation with plaque instability in internal carotid artery in humans. Two independent cohorts of atherosclerotic plaques of patients who underwent carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery were collected in two Italian hospitals (n = 15 and n = 38). The plaques were subdivided into 2 groups (symptomatic and asymptomatic plaques) according to the presence or absence of stroke. The authors observed that, among the 41 miRNAs examined, there was increased expression of 5 miRNAs (miNA-100, miRNA-127, miRNA-145, miRNA-133a, and miRNA-133b) in symptomatic compared with asymptomatic plaques. 76 It is worth mentioning that differences in the expression of miRNAs between stable and unstable plaques were not related to differences in conventional risk factors or concomitant therapies, since these variables were well balanced between the two groups. Incubation of HUVECs with miR-133 downregulated the expression of plasminogen activator inhibitor-1 (PAI-1). 76 Conclusion Despite all difficulties and challenges, it is crucial to identify dysregulated miRNAs, as it allows a better understanding of cellular and molecular mechanisms involved in CVDs. Studies on tissue and circulating miRNAs could help in the development of more accurate diagnostic and prognostic circulating markers, as well as new therapeutic strategies for different stages of CVDs. Despite advances in this field, there are still some limitations, for example, in using circulating miRNAs as biomarkers. Molecular processes that control the packing and release of extracellular miRNAs have not been fully elucidated, including mechanisms mediated or not by vesicles. Besides, detection of circulating miRNAs requires high technical skills, which could limit their use in routine laboratory use. Another limiting factor is the omnipresence of miRNAs in the circulation, requiring further investigations to identify its tissue origin. Author contributions Conception and design of the research: Fernandes-Santos C; acquisition of data, analysis and interpretation of the data, writing of the manuscript and critical revision of the manuscript for intellectual contente: Silva DCP, Carneiro FD, Almeida KC, Fernandes-Santos, C. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding This study was funded by FAPERJ. Study Association This article is part of the thesis of Doctoral submitted by Debora Cristina Pereira da Silva, from Programa de Pós‑graduação em Ciências Cardiovasculares da Universidade Federal Fluminense. 743