Triglyceride-Rich Lipoprotein Modulates Endothelial Vascular Cell Adhesion Molecule (VCAM)-1 Expression via Differential Regulation of Endoplasmic Reticulum Stress

Abstract

Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL’s atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1α (IRE1α), and downstream effectors including eukaryotic initiation factor-2α (eIF2α), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual’s TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE‐receptor, oxidative, and endoplasmic reticulum stress

“…In addition, MCP‐1 secretion is reduced by SAL in gLDL‐exposed HEC. Reported data show that eIF2α/CHOP pathway activated by ERS is important for the stimulation of VCAM‐1 and MCP‐1 production in other experimental models . Interestingly, in agreement with these studies, we have previously revealed that in HEC after 24 h incubation with gLDL, only eIF2α/CHOP pathway of the unfolded protein response remains upregulated .…”

Endoplasmic Reticulum Stress in Immunity

“…Stromal endothelial cells exposed to the oxidized lipid 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine, often found in atherosclerotic lesions, upregulate the monocyte chemoattractant CXCL3 in an XBP-1-dependent manner (141). Similarly, in response to proatherogenic triglyceride-rich lipoprotein, endothelial cells induce VCAM-1 via CHOP, potentially enhancing adhesion and diapedesis of lymphocytes, myeloid cells, and granulocytes (142). Furthermore, both muscle cells and airway epithelial cells secrete a functional leukocyte-adhesive hyaluronan matrix after exposure to various forms of ER stress (143).…”

Equol Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice by Inhibiting Endoplasmic Reticulum Stress via Activation of Nrf2 in Endothelial Cells

“…It has been confirmed that ER stress is induced in atherosclerosis lesions[24, 25]. A previous study indicated that ER stress accelerated atherosclerosis through promoting macrophage-derived foam cell formation[26], inducing apoptosis of lesion-resident macrophages[27], accelerating smooth muscle cell proliferation[28], and stimulating the secretion of inflammatory cytokines, adhesion and apoptosis in endothelial cells[29, 30]. These observations are in agreement with the results of the present study.…”