Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis

Gleissner, Christian A.; Leitinger, Norbert; Ley, Klaus

doi:10.1161/hypertensionaha.107.089854

Cited by 92 publications

(48 citation statements)

References 137 publications

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“…A key promoter of atherosclerotic inflammation including monocyte recruitment (7), macrophage survival (8), activation, and foam cell formation (9) is a modified form of low-density lipoprotein (LDL) called oxidized LDL (oxLDL). Proinflammatory cytokines and lipopolysaccharide are effective stimulators of macrophage 18 F-FDG uptake (10)(11)(12), implicating a connection of macrophage glucose metabolism to inflammatory phenotype.…”

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confidence: 99%

Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

et al. 2014

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For 18 F-FDG PET to be widely used to monitor atherosclerosis progression and therapeutic response, it is crucial to better understand how macrophage glucose metabolism is influenced by the atherosclerotic microenvironment and to elucidate the molecular mechanisms of this response. Oxidized low-density lipoprotein (oxLDL) is a key player in atherosclerotic inflammation that promotes macrophage recruitment, activation, and foam cell formation. We thus explored the effect of oxLDL on macrophage 18 F-FDG uptake and investigated the underlying molecular mechanism including the roles of hypoxia-inducible factor-1α (HIF-1α) and reactive oxygen species (ROS). Methods: RAW264.7 macrophages were stimulated with native LDL, oxLDL, or lipopolysaccharide. Cells were assessed for 18 F-FDG uptake, lactate production, membrane glucose transporter 1 (GLUT1) expression, and hexokinase activity. ROS generation, Nox expression, and HIF-1α activity were also measured. Results: oxLDL (20 μg/mL) induced a 17.5 ± 1.7-fold increase in macrophage 18 F-FDG uptake by 24 h, which was accompanied by increased lactate production, membrane GLUT1 expression, and hexokinase activity. oxLDL-stimulated 18 F-FDG uptake was completely blocked by inhibitors of Src or phosphoinositide 3-kinase. ROS generation was increased to 262.4% ± 17.9% of controls by oxLDL, and N-acetyl-L-cysteine completely abrogated both oxLDLinduced ROS production and 18 F-FDG uptake. oxLDL increased Nox2 expression, and nicotinamide adenine dinucleotide phosphate oxidase inhibition totally blocked increased ROS generation and 18 F-FDG uptake by oxLDL. Finally, there was a clear ROSdependent increase of HIF-1α accumulation by oxLDL, and silencing of HIF-1α completely abolished the metabolic effect of oxLDL. Conclusion: oxLDL is a strong stimulator of macrophage 18 F-FDG uptake and glycolysis through upregulation of GLUT1 and hexokinase. This metabolic response is mediated by Nox2-dependent ROS generation that promotes HIF-1α activation.

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Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

et al. 2014

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“…Было установлено, что при атеросклерозе многие рецепторы моноцитов активированы, в частности, интегриновый рецептор CD11/CD18 для межклеточной молекулы адгезии (ICAM) эндотелия, что играет ключевую роль в первичном развитии и прогрессировании атеросклеротических поражений [2].…”

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Activation of ganglioside GM3 biosynthesis in human blood mononuclear cells in atherosclerosis

et al. 2013

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Using blood monocytes and lymphocytes from atherosclerotic patients and healthy subjects we have investigated activity of GM3 synthase, cellular levels of ganglioside GM3 and its role in monocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC). The results showed that activity of GM3 synthase and cellular levels of ganglioside GM3 in blood mononuclear cells from atherosclerotic patients were several-fold higher than those from healthy subjects. In monocytes the activity of GM3 synthase was one an order of magnitude higher than in lymphocytes from both groups studied; this suggests the major contribution of monocytes to enhanced biosynthesis and levels of GM3 in mononuclear cells in atherosclerosis. Enrichment of monocytes from healthy subjects with ganglioside GM3 by incubation in medium containing this ganglioside increased adherence of these monocytes to HUVEC up to the values typical for monocytes from atherosclerotic patients. In addition, an increase in CD11b integrin expression was observed that was comparable to that seen in lipopolysaccharide-activated monocytes. It is suggested that in atherosclerosis the enhanced cellular levels of GM3 in monocytes and lymphocytes may be an important element of cell activation that facilitates their adhesion to endothelial cells and penetration into intima.

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“…In addition, ox-LDL initiates monocyte invasion in subendothelial space. Certainly, ox-LDL can enhance the expression of vascular cell adhesion molecule-1 (VCAM-1), 4) which assists monocytes adhesion to endothelial cells, 5,6) and initiates the formation of atherosclerotic lesions. 7) Mitogen activated protein kinase (MAPK) pathway is a key signal transduction pathway and is associated with many inflammatory diseases.…”

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Paeonol Inhibits Oxidized Low Density Lipoprotein-Induced Monocyte Adhesion to Vascular Endothelial Cells by Inhibiting the Mitogen Activated Protein Kinase Pathway

Wang

Dai

Zhong

et al. 2012

Biological & Pharmaceutical Bulletin

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Atherosclerosis is a chronic inflammatory disease characterized by increased expression of adhesion molecules, which contribute to monocytes adhesion to vascular endothelial cells (VECs). Paeonol, an active compound isolated from cortex Moutan, has been shown to have therapeutic effects on atherosclerotic animals. The present study aims to investigate whether paeonol can inhibit monocyte adhesion to vascular endothelial cells induced by oxidized Low-Density Lipoprotein (ox-LDL) and its possible therapeutic molecular mechanism. Exposure to ox-LDL (50, 100 µg/mL) induced damaged to VECs leading to decreased survival rates (p<0.01). Paeonol (7.2-18.0 µM) partially restored survival and reduced lactate dehydrogenase (LDH) release in VECs in a concentration-dependent manner (p<0.01). Adhesion of monocytes to VECs was dramatically prevented by paeonol at 21.6 and 25.2 μM (p<0.01). In addition, paeonol (14.4-21.6 μM) repressed the expression of vascular cell adhesion molecule-1 (VCAM-1) and lowered the levels of phosphor-c-Jun N-terminal kinase (P-JNK)1/2, phosphor-extracellular signal-regulated kinase (P-ERK)1/2 and P-p38 in a dose-dependent manner. The molecular effects of paeonol were more pronouced when companied with mitogen activated protein kinases (MAPKs) inhibitors. These data suggest that paeonol (10.8-25.2 μM), at certain concentrations, prevents monocyte adhesion to VEC induced by ox-LDL, probably by means of blocking one or more target proteins on MAPKs signaling pathway. These results indicate that paeonol has potential protective effects on the development of atherosclerosis.

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Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis

Cited by 92 publications

References 137 publications

Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

Activation of ganglioside GM3 biosynthesis in human blood mononuclear cells in atherosclerosis

Paeonol Inhibits Oxidized Low Density Lipoprotein-Induced Monocyte Adhesion to Vascular Endothelial Cells by Inhibiting the Mitogen Activated Protein Kinase Pathway

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Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis

Cited by 92 publications

References 137 publications

Oxidized Low-Density Lipoprotein Stimulates Macrophage 18F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

Oxidized Low-Density Lipoprotein Stimulates Macrophage 18F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

Activation of ganglioside GM3 biosynthesis in human blood mononuclear cells in atherosclerosis

Paeonol Inhibits Oxidized Low Density Lipoprotein-Induced Monocyte Adhesion to Vascular Endothelial Cells by Inhibiting the Mitogen Activated Protein Kinase Pathway

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Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

Oxidized Low-Density Lipoprotein Stimulates Macrophage ¹⁸F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation