Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Puig, Núria; Montolio, Lara; Camps‐Renom, Pol; Navarra, Laia; Jiménez‐Altayó, Francesc; Jiménez‐Xarrié, Elena; Sánchez-Quesada, José Luís; Benı́tez, Sònia

doi:10.3390/cells9030583

Cited by 38 publications

(24 citation statements)

References 56 publications

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“…Native LDL modi cation due to oxidation [90], aggregation [91], or complex formation with proteoglycans [92][93][94][95] is known to promote cholesterol accumulation in macrophages. In contrast, con uent arterial endothelial cells are resistant to cholesterol accumulation induced by any of these lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro

2021

Preprint

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Background Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. The mechanism or implication of this observation is unknown. Methods The role of tumor necrosis factor alpha (TNFɑ) in modulating low density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. Results TNFɑ promoted up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFɑ could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), RAP, or apoE depletion. Moreover, TNFɑ-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. Effects of TNFɑ included LDLR cell surface increase by 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFɑ-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFɑ on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by downstream cascade inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on transwell inserts, TNFɑ did not enhance apical (AP) to basolateral (BL) LDL cholesterol or Dil release. Conclusions It is concluded that TNFɑ promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation. This may have important implications on progression of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro

2021

Preprint

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“…Native LDL modification due to oxidation [90], aggregation [91], or complex formation with proteoglycans [92][93][94][95] is known to promote cholesterol accumulation in macrophages. In contrast, confluent arterial endothelial cells are resistant to cholesterol accumulation induced by any of these lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Okoro¹

2021

Preprint

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Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFɑ) in modulating low density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFɑ promoted up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFɑ could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), receptor associated protein (RAP), or apolipoprotein (apoE) depletion. Moreover, TNFɑ-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. Effects of TNFɑ included LDLR cell surface increase by 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFɑ-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFɑ on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on transwell inserts, TNFɑ did not enhance apical to basolateral LDL cholesterol or Dil release. It is concluded that TNFɑ promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation.

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“…Furthermore, LDL(−) also induces aggregation of platelets through the LOX-1 and PAF receptors, which promote platelet adhesion to ECs and thrombogenic state [102]. Interestingly, LDL(−) enhances the formation of triglyceride (TG)-rich lipid droplets in macrophages and releases more cytokines than copper-induced oxLDL [103].…”

Section: The Impact Of Modified Ldl and Its Components On Vascular Cellsmentioning

confidence: 99%

Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

Obama

Itabe

2020

IJMS

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Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.

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Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Cited by 38 publications

References 56 publications

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

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