Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells
Atherosclerotic artery disease is the major cause of death and an immense burden on healthcare systems worldwide. The formation of atherosclerotic plaques is promoted by high levels of low-density lipoproteins (LDL) in the blood, especially in the oxidized form. Circulating LDL is taken up by conven...
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MDPI AG
2022-01-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/2/204 |
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| author | Rusan Catar Lei Chen Hongfan Zhao Dashan Wu Julian Kamhieh-Milz Christian Lücht Daniel Zickler Alexander W. Krug Christian G. Ziegler Henning Morawietz Janusz Witowski |
| author_facet | Rusan Catar Lei Chen Hongfan Zhao Dashan Wu Julian Kamhieh-Milz Christian Lücht Daniel Zickler Alexander W. Krug Christian G. Ziegler Henning Morawietz Janusz Witowski |
| author_sort | Rusan Catar |
| collection | DOAJ |
| description | Atherosclerotic artery disease is the major cause of death and an immense burden on healthcare systems worldwide. The formation of atherosclerotic plaques is promoted by high levels of low-density lipoproteins (LDL) in the blood, especially in the oxidized form. Circulating LDL is taken up by conventional and non-classical endothelial cell receptors and deposited in the vessel wall. The exact mechanism of LDL interaction with vascular endothelial cells is not fully understood. Moreover, it appears to depend on the type and location of the vessel affected and the receptor involved. Here, we analyze how native LDL (nLDL) and oxidized LDL (oxLDL) modulate the expression of their receptors—classical LDLR and alternative LOX-1—in endothelial cells derived from human umbilical artery (HUAECs), used as an example of a medium-sized vessel, which is typically affected by atherosclerosis. Exposure of HUAECs to nLDL resulted in moderate nLDL uptake and gradual increase in LDLR, but not LOX-1, expression over 24 h. Conversely, exposure of HUAECs to oxLDL, led to significant accumulation of oxLDL and rapid induction of LOX-1, but not LDLR, within 7 h. These activation processes were associated with phosphorylation of protein kinases ERK1/2 and p38, followed by activation of the transcription factor AP-1 and its binding to the promoters of the respective receptor genes. Both nLDL-induced <i>LDLR</i> mRNA expression and oxLDL-induced <i>LOX-1</i> mRNA expression were abolished by blocking ERK1/2, p-38 or AP-1. In addition, oxLDL, but not nLDL, was capable of inducing <i>LOX-1</i> through the NF-κB-controlled pathway. These observations indicate that in arterial endothelial cells nLDL and oxLDL signal mainly via LDLR and LOX-1 receptors, respectively, and engage ERK1/2 and p38 kinases, and AP-1, as well as NF-κB transcription factors to exert feed-forward regulation and increase the expression of these receptors, which may perpetuate endothelial dysfunction in atherosclerosis. |
| first_indexed | 2024-03-10T01:44:26Z |
| format | Article |
| id | doaj.art-a1dbfa7886434e3db23dc5952ef51eea |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:44:26Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a1dbfa7886434e3db23dc5952ef51eea2023-11-23T13:17:40ZengMDPI AGCells2073-44092022-01-0111220410.3390/cells11020204Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial CellsRusan Catar0Lei Chen1Hongfan Zhao2Dashan Wu3Julian Kamhieh-Milz4Christian Lücht5Daniel Zickler6Alexander W. Krug7Christian G. Ziegler8Henning Morawietz9Janusz Witowski10Department of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyInstitute of Transfusion Medicine, Charité Universitätsmedizin Berlin, 10117 Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Medicine III, University Hospital Carl Gustav Carus Dresden, 01307 Dresden, GermanyDepartment of Medicine III, University Hospital Carl Gustav Carus Dresden, 01307 Dresden, GermanyDepartment of Medicine III, Division of Vascular Endothelium and Microcirculation, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyAtherosclerotic artery disease is the major cause of death and an immense burden on healthcare systems worldwide. The formation of atherosclerotic plaques is promoted by high levels of low-density lipoproteins (LDL) in the blood, especially in the oxidized form. Circulating LDL is taken up by conventional and non-classical endothelial cell receptors and deposited in the vessel wall. The exact mechanism of LDL interaction with vascular endothelial cells is not fully understood. Moreover, it appears to depend on the type and location of the vessel affected and the receptor involved. Here, we analyze how native LDL (nLDL) and oxidized LDL (oxLDL) modulate the expression of their receptors—classical LDLR and alternative LOX-1—in endothelial cells derived from human umbilical artery (HUAECs), used as an example of a medium-sized vessel, which is typically affected by atherosclerosis. Exposure of HUAECs to nLDL resulted in moderate nLDL uptake and gradual increase in LDLR, but not LOX-1, expression over 24 h. Conversely, exposure of HUAECs to oxLDL, led to significant accumulation of oxLDL and rapid induction of LOX-1, but not LDLR, within 7 h. These activation processes were associated with phosphorylation of protein kinases ERK1/2 and p38, followed by activation of the transcription factor AP-1 and its binding to the promoters of the respective receptor genes. Both nLDL-induced <i>LDLR</i> mRNA expression and oxLDL-induced <i>LOX-1</i> mRNA expression were abolished by blocking ERK1/2, p-38 or AP-1. In addition, oxLDL, but not nLDL, was capable of inducing <i>LOX-1</i> through the NF-κB-controlled pathway. These observations indicate that in arterial endothelial cells nLDL and oxLDL signal mainly via LDLR and LOX-1 receptors, respectively, and engage ERK1/2 and p38 kinases, and AP-1, as well as NF-κB transcription factors to exert feed-forward regulation and increase the expression of these receptors, which may perpetuate endothelial dysfunction in atherosclerosis.https://www.mdpi.com/2073-4409/11/2/204atherosclerosisendotheliumLDLLDL receptorLOX-1AP-1 |
| spellingShingle | Rusan Catar Lei Chen Hongfan Zhao Dashan Wu Julian Kamhieh-Milz Christian Lücht Daniel Zickler Alexander W. Krug Christian G. Ziegler Henning Morawietz Janusz Witowski Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells Cells atherosclerosis endothelium LDL LDL receptor LOX-1 AP-1 |
| title | Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells |
| title_full | Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells |
| title_fullStr | Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells |
| title_full_unstemmed | Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells |
| title_short | Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells |
| title_sort | native and oxidized low density lipoproteins increase the expression of the ldl receptor and the lox 1 receptor respectively in arterial endothelial cells |
| topic | atherosclerosis endothelium LDL LDL receptor LOX-1 AP-1 |
| url | https://www.mdpi.com/2073-4409/11/2/204 |
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