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 [3H]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.

Comparing the Prognostic Value of Hematological Indices in Patients With ST Segment Elevation Myocardial Infarction: “A Head to Head” Analysis

“…35 One possible explanation of the underlying mechanism is that the combination of monocyte and HDL-C may be closely linked to chronicle systemic inflammation, endothelial dysfunction, and oxidative stress. 36 Macrophages, transformed from circulating monocytes, are one of the key cell types for atherosclerotic plaque formation. During atherosclerotic plaque formation, blood monocytes are recruited into the intima and differentiate into the foam cells by taking up oxidized LDL and other lipids.…”

GPCR signalling from within the cell

“…Interestingly, many of the receptors trafficked from the cell surface are not associated with NMs but rather appear within the nucleoplasm itself ( via unknown mechanisms). These include the apelin, CCR2, vasopressin V 1A receptor, sphingosine 1‐phosphate receptor, S1P 1 , oxytocin and CXCR4 receptors (Lee et al ., ; Kinsey et al ., ; Favre et al ., ; Estrada et al ., ; Verzijl et al ., ; Don‐Salu‐Hewage et al ., ; Di Benedetto et al ., ; Sun et al ., ). Some GPCRs, however, are trafficked directly to the NM.…”

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…Interestingly, some receptors trafficked from the cell surface are not associated with nuclear membranes but rather appear within the nucleoplasm itself. These include the apelin receptor, chemokine receptor 2 (CCR2), arginine vasopressin receptor1α, sphingosine 1-phosphate receptor 1(S1P1), oxytocin receptor, and Cysteine (C)-X-C receptor 4 (CXCR4) (17, 24–32). For those GPCRs trafficked directly to the nuclear membrane, a simple diffusion-retention model has been proposed since the outer nuclear membrane is contiguous with the ER (33, 34).…”