ABC | Volume 111, Nº5, November 2018

Review Article Silva et al miRNAs and cardiovascular disease Arq Bras Cardiol. 2018; 111(5):738-746 Figure 4 – Atherosclerosis and miRNAs. Dysregulation of the expression of several miRNAs has been found in different stages of atherosclerosis formation. Some of the miRNAs involved in endothelial dysfunction and inflammation, cholesterol homeostasis, plaque development, neoangiogenesis and plaque instability and rupture are here illustrated. ENDOTHELIUM CHOLESTEROL HOMEOSTASIS PLAQUE DEVELOPMENT NEOANGIOGENESIS PLAQUE INSTABILITY AND RUPTURE miR-10a/b miR-17-3p miR-31 miR-126 miR-181b miR-33a/b miR-122 miR-21 miR-26a miR-125a-5p miR-155 miR-221 miR-27a/b miR-155 miR-210 miR-221 miR-222 miR-100 miR-127 miR-133a/b miR-145 Tissue expression profile based on diseases Ikeda et al. 55 performed a broad analysis of miRNA expression in 67 samples of left ventricular myocardium in ischemic cardiomyopathy, dilated cardiomyopathy and aortic stenosis patients. They found distinct microRNA expression profiles according to different diseases; expression of 13 miRNAs was specific to aortic stenosis, and 8 miRNAs specific to both cardiomyopathies, with no overlapping between both groups. 55 In dilated cardiomyopathy and aortic stenosis, expression of miR-1, -19a and -19b was reduced and miR-214 expression was increased; this was related to cardiac hypertrophy, with no changes in miRNA-133 and -208 expression. 55 Nevertheless, Care et al. 56 showed reduced expression of miRNA-133 in hypertrophic cardiomyopathy and atrial dilation, whereas Yang et al. 57 reported increased expression of miR-1 in ischemic cardiomyopathy. In the study by Lai et al., 53 the association of several miRNAs with HF was investigated in biopsy specimens taken from left ventricular apex during cardiac surgery. Increased expression of miR-1, -21, -23, -29, -130, -195 and -199 was found in myocardium of these patients, whereas miR-30, -133 and -208 expression was unchanged. This was associated with higher mRNA expression for caspase-3, type I and type III collagen and TGF. 53 Atherosclerosis Atherosclerosis is a chronic inflammatory disease of the artery walls in response to endothelial injury, especially in medium and large sized elastic vessels, muscular arteries and regions with disturbed laminar blood flow. It is considered the main cause of coronary artery disease, carotid artery disease, stroke and peripheral vascular disease. 58 Several evidences have shown the involvement of miRNAs in the development of atherosclerosis, in both human and animal models. MiRNAs can be categorized into miRNAs involved in endothelial dysfunction, cholesterol homeostasis, development of atherosclerotic plaque, neoangionesis and plaque instability and rupture, as described in Figure 4. Endothelium In pigs, endothelial cells from regions susceptible to atherosclerosis (aortic arch and abdominal aortic-renal artery bifurcation) showed reduced expression of miR-10a and -10b. MiR-10a inhibits some pro-inflammatory genes in endothelial cells, including vascular cell adhesion molecule-1 (VCAM‑1) and E-selectin, as well as the NF-kB pathway. 59 In rats, miR-181b regulates endothelial cell activation and vascular inflammatory response to NF-kB in the presence of pro‑inflammatory stimuli. 60 In human umbilical vein endothelial cells (HUVEC), miR-126, miR-31 and miR‑1703p also regulate vascular inflammation by controlling the expression of cell adhesion molecules – VCAM-1, intercellular adhesion molecule-1 (ICAM-1) and E-selectin. 61 Cholesterol homeostasis MiR-33a and miR-33b regulate SREBP2 and SREPB1 genes, responsible for cholesterol regulation and fatty acid metabolism, in human and mice cells. 62 Inhibition of miR‑33a inhibited atherosclerosis in mice. 63 Inhibition of miR-122 expression, which accounts for 80% of miRNAs expressed in the liver, significantly decreased cholesterol serum levels in mice and non-human primates. 64 Plaque development MiR-155 is an important regulator of the immune system and seems to be involved in acute inflammatory response. MiR-155 modulates the development of atherosclerotic plaque, lipid uptake and the inflammatory response of monocytes and macrophages that leads to foam cell formation. Among its mechanism of action, this miRNA acts as a regulator of the negative feedback in oxidized LDL-induced inflammatory response in macrophages and inhibits the release of inflammatory cytokines from macrophages, such as interleukin 6 (IL-6) and IL-8 and tumoral necrosis factor alpha (TNF- α ). 65 In peripheral blood monocytes in humans, miR-125a‑5p showed an important role in mediating lipid absorption and reducing the secretion of some inflammatory cytokines (IL-2, IL-6, TNF- α and TGF- β ) in macrophages. 66 Oxidized LDL increased the levels of miR-125a-5p, which regulates oxysterol-binding protein-related protein (ORP)-9, hence decreasing the expression of scavenger receptors (CD68) and LOX-1. 66 Similarly, miR-155 reduced oxidized LDL uptake, decreasing the expression of CD36 and LOX-1. 65 742