Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 2; p. 204
• Main Authors: Catar, Rusan, Chen, Lei, Zhao, Hongfan, Wu, Dashan, Kamhieh-Milz, Julian, Lücht, Christian, Zickler, Daniel, Krug, Alexander W, Ziegler, Christian G, Morawietz, Henning, Witowski, Janusz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.01.2022; MDPI
• Subjects: Activator protein 1; AP-1; Apoptosis; Arteriosclerosis; Atherosclerosis; Binding sites; Cardiovascular disease; Cell Survival - drug effects; Cells, Cultured; Cholesterol; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Gene expression; Gene Expression Regulation - drug effects; Humans; Kinases; LDL; LDL receptor; Lipoproteins; Lipoproteins, LDL - pharmacology; Low density lipoprotein; Low density lipoprotein receptors; LOX-1; LOX-1 protein; MAP Kinase Signaling System - drug effects; NF-kappa B - metabolism; NF-κB protein; Oxidation; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Plaques; Promoter Regions, Genetic - genetics; Protein kinase; Proteins; Receptors, LDL - genetics; Receptors, LDL - metabolism; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Transcription activation; Transcription Factor AP-1 - metabolism; Transcription factors; Umbilical Arteries - cytology; atherosclerosis; NF-κB; endothelium; LDL; AP-1; LOX-1; LDL receptor
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11020204

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 mRNA expression and oxLDL-induced mRNA expression were abolished by blocking ERK1/2, p-38 or AP-1. In addition, oxLDL, but not nLDL, was capable of inducing 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.