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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 *

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Proposed model for the impact of CCL2 on HDL internalization and cholesterol efflux and regulatory mechanisms in HCAECs. CCL2 binds to CCR2, activates p42/44 MAPK pathway, and leads to the suppression of HDL internalization and cholesterol efflux to HDL/apoA1. ApoA1, apolipoprotein AI.
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Figure 7: Proposed model for the impact of CCL2 on HDL internalization and cholesterol efflux and regulatory mechanisms in HCAECs. CCL2 binds to CCR2, activates p42/44 MAPK pathway, and leads to the suppression of HDL internalization and cholesterol efflux to HDL/apoA1. ApoA1, apolipoprotein AI.

Mentions: Intriguingly, we found that CCL2 suppressed 125I-HDL binding, cell association, HDL phospholipid and protein internalization, and [3H]cholesterol efflux in HUVECs and HCAECs. Our data showed CCR2 was activated significantly, whereas CCR3/5 was not induced by CCL2 and participated in the above process. This suggested CCL2 exhibited a particular affinity for CCR2. Further study suggested that the p42/44 MAPK pathway participated in the CCL2-induced attenuation of HDL function via CCR2 in ECs (Fig. 7).


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 *
Proposed model for the impact of CCL2 on HDL internalization and cholesterol efflux and regulatory mechanisms in HCAECs. CCL2 binds to CCR2, activates p42/44 MAPK pathway, and leads to the suppression of HDL internalization and cholesterol efflux to HDL/apoA1. ApoA1, apolipoprotein AI.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016689&req=5

Figure 7: Proposed model for the impact of CCL2 on HDL internalization and cholesterol efflux and regulatory mechanisms in HCAECs. CCL2 binds to CCR2, activates p42/44 MAPK pathway, and leads to the suppression of HDL internalization and cholesterol efflux to HDL/apoA1. ApoA1, apolipoprotein AI.
Mentions: Intriguingly, we found that CCL2 suppressed 125I-HDL binding, cell association, HDL phospholipid and protein internalization, and [3H]cholesterol efflux in HUVECs and HCAECs. Our data showed CCR2 was activated significantly, whereas CCR3/5 was not induced by CCL2 and participated in the above process. This suggested CCL2 exhibited a particular affinity for CCR2. Further study suggested that the p42/44 MAPK pathway participated in the CCL2-induced attenuation of HDL function via CCR2 in ECs (Fig. 7).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus