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

Abstract

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

Combined transcriptome and proteome analysis of yak PASMCs under hypoxic and normoxic conditions

“…OLR1 was first found in bovine aortic endothelial cells by Sawamura et al (1997) and is usually involved in regulating the metabolism of fats in the liver and mammary glands. OLR1 is also related to the with the storage of triacylglycerol, and is generally highly expressed in the lungs, liver, and adipose tissue ( Sun, Liu & Zhang, 2009 ; Catar et al., 2022 ). In recent years, OLR1 research has mainly focused on cardiovascular and metabolic diseases, such as atherosclerosis and diabetes ( Mohammed et al, 2022 ).…”

COVID-19 and Lipid Disorders

“…SARS-CoV-2 infection has been shown to activate via ACE2 NADPH oxidase (Nox) 2 and superoxide anion formation in endothelial cells [18]. Oxidation of LDL to oxLDL leads via LOX-1 activation [19] to increased ACE and angiotensin II receptor type 1 gene expression [20]. Upregulation of ACE downregulates ACE2 and vice versa ACE inhibition upregulates ACE2 [7].…”

“…Serum lipoprotein(a) [Lp(a)] did not significantly differ between COVID-19 patients and disease controls, although its concentration was found to be significantly positively associated with severity of COVID-19 illness, including acute kidney failure stage, admission disease severity, and peak severity [33]. Serum Lp(a) concentrations were higher in patients with recurrent cerebral venous sinus thrombosis (CVST) compared to patients without; that is, 28 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) mg/dl versus 14 (9-25) mg/dl [34]. The importance of elevated serum Lp(a) as a potential risk factor for CVST maybe even higher in patients with SARS-CoV-2 infection.…”

Schisanhenol amelioratesoxLDL‐caused endothelial dysfunction by inhibitingLOX‐1 signaling

“…After binding with its ligand oxLDL, LOX-1 activates p38MAPK and NF-κB. 11 The activation of LOX-1-modulated NF-κB results in an enhanced expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). 12 Moreover, inflammatory cytokines are reported to enhance LOX-1 expression levels in SMCs.…”