Effect of Glucose Concentration on Foam Cell Formation in THP-1 Cells

Naito, Takashi; Oikawa, Shinichi; Kotake, Hidetoshi; Hayasaka, Kazuki; Toyota, Takayoshi

doi:10.5551/jat1994.8.55

Cited by 10 publications

(6 citation statements)

References 35 publications

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“…Evidence that incubation of macrophages in high glucose conditions leads to increased intracellular accumulation of cholesterol ester 52 suggests a role for hyperglycemia in foam cell formation. Like other scavenger receptors, LOX-1 is highly expressed in macrophages present in human atherosclerotic lesions 21 and thus may play a role in macrophage foam cell formation.…”

Section: Discussionmentioning

confidence: 99%

Glucose Enhances Human Macrophage LOX-1 Expression

Sawamura

Renier

2004

Circulation Research

145

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Abstract-Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose-and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-B (NF-B), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKC␤ 2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKC␤ inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-B and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis. Key Words: macrophages Ⅲ lectin-like oxidized low-density lipoprotein receptor-1 Ⅲ glucose Ⅲ diabetes Ⅲ foam cell formation T he prevalence, incidence, and mortality from all forms of cardiovascular diseases are increased in patients with diabetes. 1 Among the cardiovascular risk factors documented in diabetes, hyperglycemia appears as an independent risk factor for diabetic macrovascular complications. 2 Mechanisms through which hyperglycemia may promote the development of diabetic cardiovascular disease include glycoxidation and lipoxidation, increased oxidative stress, and protein kinase C (PKC) activation. [3][4][5][6][7][8] One of the earliest events in atherogenesis is the accumulation of oxidized LDL (oxLDL) in the intima and the subsequent uptake of this modified lipoprotein by macrophages, leading to foam cell formation. 9 One limiting factor for oxLDL uptake by endothelial cells is lectin-like oxLDL receptor-1 (LOX-1), a newly identified vascular receptor for oxLDL. 10 -12 Accumulating evidence indicates a key role for LOX-1 in atherogenesis. First, uptake of oxLDL by endothelial cells through LOX-1 induces endothelial dysfunction. Second, the two main LOX-1 ligands, oxLDL and advanced glycation end products (AGE), are implicated in the pathogenesis of atherosclerosis. 5,9 Third, expression of LOX-1 b...

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Section: Discussionmentioning

confidence: 99%

Glucose Enhances Human Macrophage LOX-1 Expression

Sawamura

Renier

2004

Circulation Research

145

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“…Both α-tocopherol and probucol significantly inhibited the cytotoxicity enhanced by ASA, suggesting that the augmentative effect of ASA on OxLDL-induced cytotoxicity is due to its pro-oxidant property. We also investigated whether a high glucose condition could af- fect ASA's effect on cytotoxicity induced by OxLDL, because it has been reported that elevated levels of glucose in the diabetic state increase LDL lipid peroxidation (16,17) and cholesterol ester synthesis in macrophages (18). The cytotoxicity was more apparent in the medium containing 400 mg/dl (22.2 mM) glucose than 200 mg/dl (11.1 mM), although the difference did not reach statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Ascorbic Acid Augments Cytotoxicity Induced by Oxidized Low-Density Lipoprotein.

Ashidate

Kawamura

Tohda

et al. 2003

JAT

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Although ascorbic acid (ASA) is known as a water-soluble antioxidant, we found that it accelerated the cytotoxicity induced by oxidized low-density lipoprotein (OxLDL) in vitro. This suggests that ASA may enhance the oxidation of LDL to augment the atherogenic activities of OxLDL under certain conditions. Thus, this study was designed to investigate the underlying mechanism that ASA enhances OxLDL-induced cytotoxicity. ASA enhanced the cytotoxicity of macrophage cell line (J774) induced by OxLDL in a dose-dependent manner, whose effect was more apparent in high glucose concentration in the medium. The ASA-induced enhancement in cytotoxicity was inhibited by the presence of lipid-soluble antioxidants, such as alpha-tocopherol and probucol, suggesting that the pro-cytotoxic effect by ASA is likely due to its pro-oxidant property. We also investigated the effects of ASA at different time points on the Cu2+-mediated oxidation of LDL. ASA decreased the rate of conjugated dienes formation when added at the early phase of oxidation, whereas it increased when added at the late phase of oxidation. These data suggest that ASA may act as a pro-oxidant under the condition of extensive LDL oxidation. To prevent oxidation stress, ASA would be better used together with lipid-soluble antioxidants for antioxidant therapies.

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“…While Tsukamoto et al failed to demonstrate a role of LOX-1 in the progression of macrophages to foam cell formation in vitro [63], other investigators have proposed a role for this receptor in lipid core [64] and foam cell formation [38]. Previous data have shown that incubation of macrophages with high glucose leads to increased intracellular accumulation of cholesterol ester [65], thus suggesting a role for hyper- hyper-glycemia in foam cell formation. Molecular mechanisms by which glucose promotes the accumulation of cholesterol in macrophages include up-regulation of CD36 and SR-A [66][67], two major determinants of oxLDL uptake by macrophages [68].…”

Section: Regulation Of Vascular Lox-1 In Diabetes-role Of Metabolic Fmentioning

confidence: 92%

Diabetic Vasculopathy and the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1)

Renie¹,

Maingrette²,

2007

CDR

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Type 2 diabetes is associated with an increased incidence of coronary heart disease and cardiovascular complications. One crucial step in the initiation and progression of atherosclerosis is the unregulated uptake of oxidized low-density lipoprotein (oxLDL) by vascular wall components through scavenger receptors. Identification of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as the major receptor for oxLDL in endothelial cells has provided a new clue to the mechanisms involved in oxLDL accumulation in the vessel wall. This receptor, by facilitating the uptake of oxLDL, induces endothelial dysfunction and mediates numerous oxLDL-induced proatherogenic effects. Besides endothelial cells, LOX-1 is also expressed by smooth muscle cells and macrophages. In these cells, LOX-1 may function as a scavenger receptor and promote foam cell formation. Notably, LOX-1 is induced by multiple stimuli relevant to atherogenesis and inflammation and is up-regulated in various proatherogenic conditions, including diabetes. As such, activation of vascular cells by oxLDL through LOX-1 may be relevant to the development and progression of human diabetic vasculopathy. This review summarizes recent advances related to the role of LOX-1 in atherosclerosis, its regulation by metabolic and inflammatory factors relevant to diabetes and the impact of these factors on LOX-1-mediated proatherogenic events linked to diabetic vasculopathy.

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Effect of Glucose Concentration on Foam Cell Formation in THP-1 Cells

Cited by 10 publications

References 35 publications

Glucose Enhances Human Macrophage LOX-1 Expression

Glucose Enhances Human Macrophage LOX-1 Expression

Ascorbic Acid Augments Cytotoxicity Induced by Oxidized Low-Density Lipoprotein.

Diabetic Vasculopathy and the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1)

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