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Highly Upregulated Expression of CD36 and MSR1 in Circulating Monocytes of Patients with Acute Coronary Syndromes

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Highly Upregulated Expression of CD36 and MSR1 in Circulating Monocytes of Patients with Acute Coronary Syndromes Protein J (2012) 31:511–518 DOI 10.1007/s10930-012-9431-8 Highly Upregulated Expression of CD36 and MSR1 in Circulating Monocytes of Patients with Acute Coronary Syndromes Michal Piechota • Anna Banaszewska • Joanna Dudziak • Marek Slomczynski • Robert Plewa Published online: 5 July 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Acute Coronary Syndromes (ACS) are a group that both investigated receptors are involved in the devel- of disorders caused by the significant reduction of circu- opment and/or progression of ACS. lation in coronary arteries. The most common reason of the dysfunction is a blood clot formed in place of plaque Keywords Atorvastatin Á Acute Coronary Syndromes Á rupture. The role of scavenger receptors in development Monocytes Á CD36 Á MSR1 and progression of atherosclerosis has been confirmed in many animal experiments, however the knowledge about Abbreviations contribution of the receptors in the development of ACS HMG-CoA 3-Hydroxy-3-methylglutaryl-CoA symptoms in humans still remains insufficient. The aim of CD36 Macrophage scavenger receptor class B this work was to define the expression of two scavenger MSR1 Macrophage scavenger receptor class A receptors: CD36 and MSR1 in monocytes of patients with LDL Low density lipoprotein ACS after the onset of symptoms and after the 6 months of oxLDL Oxidized low density lipoprotein treatment. The analysis of CD36 and MSR1 expression was ROS Reactive oxygen species carried out with the use of real-time PCR and flow acLDL Acetylated low density lipoprotein cytometry. Analyses of lipid and glucose concentration in ACS Acute Coronary Syndromes blood and the level of inflammatory markers in plasma STEMI Acute myocardial infarction with ST were performed additionally for all ACS patients. All data elevation obtained during the research were analyzed using statistical NSTEMI Acute myocardial infarction without ST tests, such as Mann Whitney test, Wilcoxon test, or cor- elevation relation. In all patients with symptoms of ACS the amount PBGD Porphobilinogen deaminase of CD36 and MSR1 mRNA in circulating monocytes, as HRPO Horseradish peroxidase well as the density of both receptors on the cells surface FSD Fluorescent surface density was significantly higher. Re-analysis of subjects after CRP C-reactive protein 6 months of treatment, showed a significant decrease in the CD36 and MSR1 expression in all patients who received atorvastatin. The results of presented studies demonstrate 1 Introduction & M. Piechota ( ) Á A. Banaszewska Á R. Plewa Acute Coronary Syndromes (ACS) are a group of disorders Department of Animal Physiology and Development, Faculty of Biology, Adam Mickiewicz University, that can be caused by a significant reduction of blood flow Umultowska 89 Str., 61-614 Poznan, Poland in coronary arteries due to narrowing or blockage of the e-mail: [email protected] vessels. The most common reason of the vessel dysfunction is the development of atherosclerotic lesions and a blood J. Dudziak Á M. Slomczynski Department of Cardiology, Jozef Strus Municipal Hospital, clot formed in place of plaque rupture [2, 39]. Oxidised Szwajcarska 3 Str., 61-285 Poznan, Poland lipoproteins (oxLDL) are the major factor responsible for 123 512 M. Piechota et al. the initiation and the acceleration of atherosclerosis. The investigate alterations in the receptors expression in processes activated by oxLDL are: endothelial dysfunction, patients after the onset of the ACS symptoms. In the second expression of adhesion molecules, synthesis of chemoat- part the experiments were repeated after the 6 months of tractants and proinflammatory cytokines, or activation of atorvastatin therapy to determine the effect of treatment on monocytes and smooth muscle cells to migration into the the CD36 and MSR1 expression in monocytes. area of inflammation [4, 6, 10, 21]. Monocyte-derived macrophages are able to bind and accumulate of modified lipoproteins through the scavenger receptors-mediated 2 Materials and Methods endocytosis [14–16, 34]. That is the main mechanism responsible for the formation of atherosclerotic plaque, 2.1 Investigated and Control Group because macrophages filled with cholesterol esters trans- form into foam cells and form the lipid core of the plaque Presented studies were carried out on the group of 100 [3, 29]. Scavenger receptors family is a large group of patients with atherosclerosis, hospitalized for the onset of proteins, divided into six classes (from A to F). All proteins symptoms of ACS, defined as acute myocardial infarction are able to recognize a large variety of ligands, such as: with ST elevation (STEMI) or without (NSTEMI). The oxidized or acetylated LDL lipoproteins, polyanions, or whole group consisted of 32 females and 68 males, aged apoptotic cells [11, 37]. The CD36, a type B scavenger from 33 to 78 years old (average 64). In 66 individuals receptor, and the MSR1, a type A, are the main receptors additional disorders were diagnosed also, such as diabetes responsible for the uptake of modified lipproteins by mellitus type 2 (NIDDM)—34 cases, arterial hypertension macrophages [12, 33, 42]. Both proteins are able to remove (HTN)—56 cases, or obesity—14 cases. Before hospital- 70–90 % of modified LDLs, however CD36 is a receptor ization none of the patients received statins and after the responsible for oxLDL degradation, while the MSR1 is onset of ACS symptoms in all analyzed cases the treatment mainly involved in the uptake of acetylated lipoproteins with statins was applied. The atorvastatin was received by (acLDL) [28]. 20 patients from the investigated group, in a dose of 40 mg The most common drugs used in the treatment of per day. 40 control subjects were also investigated, 20 hypercholesterolemia and the reduction of the risk of car- females and 20 males, ranging from 26 to 54 years (aver- dio-vascular events in patients with ischemic heart disease age 37). The main criteria for selecting the control group are statins. The main therapeutic action of the drugs is the were normal laboratory findings, such as the lipid con- lowering of endogenous cholesterol synthesis through the centration in plasma, blood glucose level, C-reactive pro- inhibition of 3-hydroxy-3-methylglutaryl coenzyme A tein (CRP) level in plasma and good general health. reductase (HMG-CoA reductase)—the key enzyme of the The material in the investigations presented was fresh process [7, 27]. Recent studies on the lipid lowering drugs patient’s anticoagulated blood taken at the latest 24 h after showed also a wide range of pleiotropic activities of statins the onset of ACS symptoms, and after 6 months of therapy that include enhancing of endothelial differentiation and with atorvastatin. The blood was used to extract DNA and stabilization [5, 38], reduction of the expression of adhe- RNA, to implement the molecular analyses, such as real- sion molecule on the endothelial surface, suppression of time PCR or flow cytometry, and to perform the basic monocyte/macrophage activation and differentiation [9, 18], laboratory tests, such as blood lipid concentration, blood inhibition of smooth muscle cell migration and proliferation, glucose level or the level of C-reactive protein (CRP) in or stabilisation of atherosclerotic plaque [19, 25, 36, 43]. A plasma. very important object in the research on additional activities of statins is the influence of the treatment on the uptake of modified lipoproteins by macrophages. Statins are able to 2.2 Monocyte Isolation reduce the level of LDL modifications due to their lipid- lowering activity and through the reduction of reactive The first step of the analysis was to separate the monocytes oxygen species (ROS) concentration in plasma [1, 17, 23, from other blood cells by density-gradient centrifugation in 26]. However the influence of the drugs on the expression of Ficoll-Pague PLUS (GE Healthcare) and magnetic sepa- scavenger receptors, the process of oxLDL accumulation ration with DynabeadsÒ CD14 (Invitrogen). The isolation and the foam cell formation remains unclear and is con- was performed according to the manufacturers’ protocol. stantly investigated [20, 30]. Peripheral blood mononuclear cells obtained after ficoll The aim of this work was to investigate the expression centrifugation were incubated with the superparamagnetic of CD36 and MSR1 scavenger receptors in monocytes polystyrene beads coated with monoclonal anti-CD14 isolated directly from fresh anticoagulated blood of antibodies and next the CD14? cells (monocytes) were patients with ACS. The purpose of the first part was to separated by placing the sample in a strong magnetic field. 123 Highly Upregulated Expression of CD36 and MSR1 513 2.3 RNA Extraction and cDNA Synthesis under conditions defined by manufacturers, and then pre- pared for analysis through lysis of erythrocytes (formic Purified monocytes were used directly to the total RNA acid), leukocytes stabilization (PBS buffer) and parafor- isolation using TRI REAGENTÒ BD (Sigma Aldrich). The maldehyde fixation, using IMMUNOPREPTM Kit (Beck- procedure was performed according to the manufacturer’ man Coulter). All analyses were performed using the Cell procedure which was designed for RNA extraction from Lab Quanta flow cytometer (Beckman Coulter). blood cells, based on the single-step RNA isolation reported by Chomczynski and Sacchi [8]. After the 2.6 Quantitative Determination of Oxidized LDL extraction the concentration of RNA in samples was esti- in Plasma mated, by micro-volume UV-Vis spectroscopy (NanoDrop; Thermo Scientific). The amount containing 500 ng of RNA For all patients the analysis of oxidized LDLs concentra- was used to reverse transcription PCR (RT-PCR) reaction. tion in plasma with the use of enzyme immunoassay: The synthesis of complementary DNA (cDNA) was per- Oxidized LDL ELISA (Biomedica) was also performed. In formed in a total volume of 20 ll, using oligo(dT)18 primer the assay polyclonal anti-oxLDL antibodies are absorbed (100 ng/ll), RNase free, DEPC treated water and Revert- into microwells. Modified lipoproteins presented in sample AidTM M-MuLV Reverse Transcriptase (Fermentas).
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