title: CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells.
abstract: High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.
authors.affiliation: From the Cardiovascular Medicine Department.
authors.forename: Run-Lu
authors.initials: RL
authors.lastname: Sun
authors.affiliation: Intensive Care Unit, and.
authors.forename: Can-Xia
authors.initials: CX
authors.lastname: Huang
authors.affiliation: Comprehensive Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Bao
authors.affiliation: the Graceland Medical Center, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
authors.forename: Jie-Yu
authors.initials: JY
authors.lastname: Jiang
authors.affiliation: From the Cardiovascular Medicine Department.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Medicine Department, the Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 51020, China.
authors.forename: Shu-Xian
authors.initials: SX
authors.lastname: Zhou
authors.affiliation: the Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, China, and.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Cai
authors.affiliation: the Centers for Metabolic and Cardiovascular Research, Departments of Pharmacology, Temple University, Philadelphia, Pennsylvania 19140.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Medicine Department, the Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 51020, China, dr_wjf@hotmail.com.
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Medicine Department, the Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 51020, China, zzhangyuling@126.com.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Zhang
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D008075:Lipoproteins, HDL; D054390:Receptors, CCR2; D002784:Cholesterol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CC-chemokine ligand 2 (CCL2); atherosclerosis; cholesterol metabolism; endothelial cell; high-density lipoprotein (HDL); mitogen-activated protein kinase (MAPK)