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Extracellular-Vesicle Containing Mirna-503-5P Released by Macrophages Contributes to Atherosclerosis

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Extracellular-Vesicle Containing Mirna-503-5P Released by Macrophages Contributes to Atherosclerosis www.aging-us.com AGING 2021, Vol. 13, No. 8 Research Paper Extracellular-vesicle containing miRNA-503-5p released by macrophages contributes to atherosclerosis Yuquan Wang1, Zhengmin Xu2, Xiaoli Wang2, Jiankang Zheng1, Lihan Peng1, Yunfei Zhou3, Yongyan Song4, Zhan Lu1 1Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, P. R. China 2Department of Pharmacy, North Sichuan Medical College, Nanchong 637000, P. R. China 3Department of Thoracic Surgery, Dazhou Central Hospital, Dazhou 635000, P. R. China 4School of Preclinical Medicine, and Nanchong Key Laboratory of Metabolic Drugs and Biological Products, North Sichuan Medical College, Nanchong 637000, P. R. China Correspondence to: Yongyan Song, Zhan Lu; email: [email protected], https://orcid.org/0000-0001-6886- 0873; [email protected], https://orcid.org/0000-0002-3102-123X Keywords: atherosclerosis, macrophage, extracellular vesicle, microRNA-503-5p, endothelial cells Received: February 17, 2020 Accepted: May 27, 2020 Published: April 19, 2021 Copyright: © 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Endothelial dysfunction, and the differentiation of smooth muscle cells (SMCs) into proliferative, secretory phenotypes, are two major pathophysiological processes in atherosclerosis. SMCs have the potential to recruit macrophages in atherosclerotic plaques, in which macrophages drive inflammatory responses. In this study, we found that microRNA-503-5p (miR-503-5p) was enriched in either extracellular vesicles (EVs), secreted by oxidized low-density lipoprotein-treated macrophages, or the EVs from peripheral blood mononuclear cells of atherosclerosis patients. miR-503-5p was transferred intercellularly from macrophages to the co-cultured human coronary artery endothelial cells (HCAECs) and HCASMCs via EVs, thus reducing the proliferative and angiogenic abilities of HCAECs and accelerating the proliferative and migrating abilities of HCASMCs. Smad family members 1, 2 and 7 were negatively regulated by miR-503-5p in HCAECs and HCASMCs. miR-503-5p was verified as an enhancer of inflammatory cytokines and adhesion molecules released by macrophages, in part via the down-regulation of smad family members 1, 2 and 7. The inhibition of miR-503-5p by lentivirus reduced atherosclerotic lesion formations in the aorta of atherosclerotic mice. Our work demonstrated a miR-503-5p- and EV-mediated mechanism for macrophage communication with HCAECs and HCASMCs in atherosclerosis. miR-503-5p is pro-atherosclerotic stimuli that may be a therapeutic target for atherosclerosis treatment. INTRODUCTION initiated by the intimal retention and modification of cholesterol-loaded lipoproteins, followed by the secretions Atherosclerosis is a disease caused by lipid-evoked of ECs and SMCs, recruitment of monocytes, and inflammatory responses of vascular walls, orchestrated by accumulation of inflammatory cells, extracellular matrix the complicated interactions among different types of cells and lipids in the tunica intima [3]. Oxidized low-density including: endothelial cells (ECs), smooth muscle cells lipoprotein (ox-LDL) is a well-known risk factor for (SMCs) and macrophages [1]. Due to facilitated roles of atherosclerosis progression [4]. Ox-LDL regulates the low endothelial shear stress produced by turbulent blood adherence activity between endothelial cells and flow in atherosclerosis formation, ECs could affect monocytes, which recruit monocyte-secreted macro- atherosclerosis formation via affecting endothelial shear phages into vessel walls and contribute to foam cell stress [2]. It has been reported that atherosclerosis is formation of macrophages to affect the progression of www.aging-us.com 12239 AGING atherosclerosis [5]. Macrophages, which are scattered collected from patients with atherosclerosis and healthy around the sites of plaque build-up, play vital roles in the individuals to determine the expression of miR-503-5p, initiation and progression of all atherosclerosis [6]. Thus, smad/TGF-β signaling pathway molecules (smad7, it is imperative to further investigate the underlying smurf1, smurf2, and TGF-β1) using reverse mechanisms of interactions among macrophages, ECs, transcription-quantitative polymerase chain reaction and SMCs in atherosclerosis. (RT-qPCR). The findings displayed that compared with healthy individuals, the expression of miR-503-5p and Extracellular vesicles (EVs) are lipid-bilayer hetero- TGF-β1 was increased at different degrees in patients geneous particles of 20 nm to 2 µm in size, are involved with coronary atherosclerosis, cerebral atherosclerosis, in atherosclerosis-related processes, such as endothelial peripheral atherosclerosis, combined coronary athero- dysfunction, inflammation of vascular wall, and vascular sclerosis and peripheral atherosclerosis, and combined remodeling [7]. EVs can be transferred between cells and cerebral atherosclerosis with peripheral atherosclerosis, encompass proteins, messenger RNAs (mRNAs), and while the expression of smad7, smurf1, and smurf2 was microRNAs (miRNAs), and they can be secreted from decreased at different degrees (p < 0.05) (Figure 1A, ECs, SMCs, and macrophages to influence the 1B), which showed a certain linear correlation (Figure development of atherosclerosis [8]. miRNAs refer to 1C). small non-coding RNA molecules, which serve as regulators of protein expression via the degradation of miR-503-5p had the ability to regulate human targeted mRNA or the blockade of protein translation [9]. coronary artery (HCA) ECs and SMCs A recent study has demonstrated that miRNAs are able to modulate cellular and molecular processes in the In order to study the effects of miR-503-5p on HCAECs development of atherosclerosis [10]. He et al. have and HCASMCs, HCAECs and HCASMCs were revealed that miR-155 is transferred to human monocytic initially treated with exogenous miR-503-5p mimic, THP1 cells with EVs as cargos to exert effects on the exogenous miR-503-5p inhibitor, miR-mimic negative progression of atherosclerosis [1]. The roles of control (NC), and miR-inhibitor NC. RT-qPCR showed macrophage-derived EVs carrying miR-503 in increased expression of miR-503-5p in HCAECs and atherosclerosis have also been demonstrated in previous HCASMCs treated with exogenous miR-503-5p mimic, evidence [11]. In addition, microarray analysis in the and decreased expression of miR-503-5p in HCAECs present study has demonstrated that miR-503-5p could and HCASMCs treated with exogenous miR-503-5p target smad7 and smurf1/smurf2. Accumulating evidence inhibitor (p < 0.05) (Figure 2A). Cell counting kit-8 has confirmed that miR-503 serves as a regulator in (CCK-8), transwell chamber assays, scratch test, smurf2 expression and the transforming growth factor-β Matrigel-based angiogenesis assays, and flow cytometry (TGF-β) signaling pathway [12]. TGF-β, induced by revealed that the overexpression of miR-503-5p could inflammatory cells, including macrophages and SMCs, is suppress the proliferative, migrating, and angiogenic implicated in atherosclerosis [13, 14]. Smad7 is regarded abilities of HCAECs and promote their apoptosis, while as a downstream suppressive Smad in TGF-β signaling enhancing proliferation and migration of HCASMCs (p and participates in atherosclerosis by affecting a series of < 0.05). However, the downregulation of miR-503-5p biological processes, including fibrosis and inflammation exerted reverse effects (p < 0.05) (Figure 2B–2F). These [15]. However, the roles of macrophage-derived EVs results suggested the suppressive effects of miR-503-5p carrying miR-503-5p in atherosclerosis via Smad7- on proliferation, migration, and angiogenesis of Smurf1/Smurf2-TGF-β axis have not been investigated HCAECs and promotive effects of miR-503-5p on yet. Therefore, we constructed models with macrophages proliferation and migration of HCASMCs. -/- treated with ox-LDL and ApoE mice fed with high-fat diet to explore the specific regulatory mechanism of EVs- miR-503-5p downregulated smad7, smurf1/smurf2 containing miR-503-5p from macrophages as a mean to and reduced the ubiquitination of TGF-β1 receptor communicate with ECs and SMCs in the biology of atherosclerosis. The microarray data GSE9490, downloaded from GEO database (https://www.ncbi.nlm.nih.gov/gds/?term=), RESULTS were analyzed to screen the differentially expressed genes (|logFC| > 1, p < 0.05). smad7 was downregulated Expression patterns of miR-503-5p, smad7, smurf1, in DL-homocysteine-induced atherosclerosis samples and smurf2 in plasma-EVs of patients with when compared with the normal samples (p < 0.05) atherosclerosis (Figure 3A). R language was utilized to identify the selected gene expression in mouse atherosclerosis- We first collected detailed information of patients with related microarray data GSE2372 (|logFC| > 1, p < atherosclerosis (recorded in Table 1). Plasma was 0.05). There were 6 samples in microarray data www.aging-us.com 12240 AGING Table 1. Clinical data collected from patients with AS. Index AS group (n = 53) Expression of miR-503-5p p Age 0.598 >45 38 3.702 ± 0.681 ≤45 15 3.583 ± 0.860 Sex 0.984 Male 29 3.670 ± 0.741 Female 24 3.666 ± 0.730 Risk factors Hypertension 0.047 Yes 10 3.258 ± 0.747 No 43 3.764 ± 0.699 Diabetes 0.004 Yes 11 3.124 ± 0.281 No 42 3.811 ± 0.745 Hyperlipemia 0.010
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