Glucose-Modified Low Density Lipoprotein Enhances Human Monocyte Chemotaxis

Millican, Stephanie A.; Schultz, Donna; Bagga, M.; Coussons, Peter J.; Müller, Karin H.; Hunt, James V.

doi:10.3109/10715769809066890

Cited by 30 publications

(24 citation statements)

References 43 publications

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“…Both native and oxidised LDL bind to mesangial matrix in vitro [24]; therefore, it is possible that mesangial cells in vivo are exposed to both native and oxidised LDL. Glycated LDL has been shown to induce functional changes in various cell types, including enhanced chemotactic properties in monocytes [25,26], stimulated migration and proliferation of smooth muscle cells [27], and increased platelet aggregation, NO production and Ca 2+ -ATPase activity [26,28]. Some information on the effect of native and oxidised LDL in promoting IL6 production in HMCs is available [20], while an extensive comparison of the biological activity of different LDL particles, including glycated LDL, has not been previously performed.…”

Section: Discussionmentioning

confidence: 99%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

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Aims/hypothesis Inflammation is a mechanism of glomerular damage in chronic glomerulopathies. LDL may increase the production of inflammatory cytokines in renal tissues. However, the relative role of native, oxidised and glycated LDL in promoting this process has been only partially elucidated. Methods We tested the inflammatory and proapoptotic effects of native, oxidised and glycated LDL in human mesangial cells (HMCs) by measuring levels of IL6, CD40 and macrophage migration inhibitory factor (MIF) genes, MIF protein, release of IL6, soluble CD40, fibronectin and laminin, early and late apoptosis, and extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation. Results IL6 and CD40 mRNA were dose-dependently upregulated by all three species; this was closely paralleled by their increased release. MIF mRNA was potently stimulated by modified LDL, as confirmed by immunostaining. Fibronectin and laminin release was stimulated by both oxidised and glycated, but not native, LDL. All LDL species induced some increase in late, but not early, apoptosis, and similarly activated JNK2/3 phosphorylation; in contrast, ERK1/2 phosphorylation was more strongly upregulated by oxidised than either native or glycated LDL.Conclusions In HMCs, the production and release of IL6 and CD40 is stimulated by both native and modified LDL, while MIF is more strongly stimulated by oxidised LDL. Regarding the pattern of mesangial expansion, fibronectin and laminin are upregulated by oxidised and glycated LDL. Apoptosis, if modest, is induced by all species. Intracellular signalling of native and modified LDL involves JNK2/3 and, perhaps more specifically, ERK1/2. Tight control of the lipid profile may be useful in preserving kidney function in patients with metabolic alterations.

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Section: Discussionmentioning

confidence: 99%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

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“…28 Glycation increases the chemotactic activity of LDL for monocytes, which promotes the deposition of monocytes on the endothelial surface. 29 Previous studies by our group indicated that glycated LDL augmented PAI-1 production and reduced tPA generation in vascular ECs. 13 Imbalance between EC-derived PAI-1 and tPA potentially reduces intravascular fibrinolytic activity and enhances thrombotic tendency.…”

Section: Discussionmentioning

confidence: 99%

Impact of Antioxidants and HDL on Glycated LDL–Induced Generation of Fibrinolytic Regulators From Vascular Endothelial Cells

Ren

Shen

2000

ATVB

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Abstract-Hyperglycemia and dyslipoproteinemia are biochemical markers of diabetes mellitus (DM). Elevated levels of plasminogen activator inhibitor-1 (PAI-1) with and without reduction of tissue plasminogen activator (tPA) in plasma have been frequently found in patients with DM. Our previous studies indicated that glycation enhances low density lipoprotein (LDL)-induced production of PAI-1 and further decreases tPA generation in vascular endothelial cells (ECs). The present study demonstrated that treatment with antioxidants, butylated hydroxytoluene or vitamin E, blocked native LDL-and glycated LDL-induced changes in PAI-1 and tPA generation in ECs. Native or glycated high density lipoprotein (HDL) did not significantly alter tPA generation in ECs. Glycated but not native HDL (Ն100 g/mL) moderately increased PAI-1 release from ECs. Cotreatment with native or glycated HDL inhibited LDL-induced or glycated LDL-induced changes in PAI-1 and tPA generation in ECs. The abundance of conjugated dienes was increased in glycated or EC-modified LDL. Treatment with butylated hydroxytoluene, vitamin E, or HDL reduced the abundance of conjugated dienes in glycated or EC-modified LDL. The effects of antioxidants and HDL on LDL-induced or its glycated LDL-induced changes in the generation of PAI-1 and tPA were also found in cultured human coronary artery ECs. The findings of the present study suggest that antioxidants and HDL may attenuate native LDL-or glycated LDL-induced changes in the generation of fibrinolytic regulators from vascular ECs, which possibly results from their inhibition on the lipid peroxidation of LDL particles. Treatment with antioxidants or hypolipidemic agents potentially improves fibrinolytic activity and reduces thrombotic tendencies in patients with DM. Key Words: LDL Ⅲ glycation Ⅲ antioxidants Ⅲ HDL Ⅲ plasminogen activator inhibitor-1 H yperglycemia and dyslipoproteinemia, 2 major biochemical markers in diabetes mellitus (DM), have been implicated in the development of cardiovascular complications in patients with DM. Intravascular thrombosis plays a critical role in the development of ischemic events with and without the presence of atherosclerotic lesions. The formation of thrombus in the vasculature mainly depends on the balance between coagulation and fibrinolysis. The release of fibrinolytic activity from the vascular wall responding to temporary occlusion was impaired in patients with DM. 1,2 The production of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in vascular endothelial cells (ECs) is modulated by thrombin, 3 glucose, 4 proinsulin, 5 growth factors, 6 and several types of plasma lipoproteins. [7][8][9][10][11][12][13] Elevated levels of glycated LDL were detected in the plasma of patients with DM. 14,15 Previous studies by our group demonstrated that glycation enhanced LDL-induced overproduction of PAI-1 and further reduced the generation of tPA from cultured vascular ECs. 13 Glycation increases the oxidative stress of lipoproteins. 16 Treatment with...

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“…Hyperglycemia, in fact, induces an increase in nonenzymatically glycated LDL (glycLDL), which renders them more susceptible to oxidative stress [38,39]. Moreover, glycLDL may cause platelet dysfunction by an increase in intracellular Ca 2+ concentration and platelet NO production, as well as inhibition of the platelet membrane -ATPase) activity, activation of protein kinase C (PKC), decreased production of nitric oxide (NO), increased formation of reactive oxygen species (ROS) and nonenzymatic glycation of platelet membrane glycoproteins (GPs).…”

Section: Metabolic Alterationsmentioning

confidence: 99%

Platelet activation in type 2 diabetes mellitus

Ferroni¹,

Basili

Falco

et al. 2004

Journal of Thrombosis and Haemostasis

395

288

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The abnormal metabolic state that accompanies diabetes renders arteries susceptible to atherosclerosis, being capable of altering the functional properties of multiple cell types, including endothelium and platelets. In particular, an altered platelet metabolism and changes in intraplatelet signaling pathways may contribute to the pathogenesis of atherothrombotic complications of diabetes. A variety of mechanisms may be responsible for enhanced platelet aggregation. Among them, hyperglycemia may represent a causal factor for in vivo platelet activation, and may be responsible for nonenzymatic glycation of platelet glycoproteins, causing changes in their structure and conformation, as well as alterations of membrane lipid dynamics. Furthermore, hyperglycemia-induced oxidative stress is responsible for enhanced peroxidation of arachidonic acid to form biologically active isoprostanes, which represents an important biochemical link between impaired glycemic control and persistent platelet activation. Finally, increased oxidative stress is responsible for activation of transcription factors and expression of redox-sensitive genes leading to a phenotypic switch of endothelium toward an adhesive, prothrombotic condition, initial platelet activation, adhesion and subsequent platelet aggregate formation. All this evidence is strengthened by the results of clinical trials documenting the beneficial effects of metabolic control on platelet function, and by the finding that aspirin treatment may even be more beneficial in diabetic than in high-risk non-diabetic patients. Attention to appropriate medical management of diabetic patients will have great impact on long-term outcome in this high-risk population. © 2004 International Society on Thrombosis and Haemostasis

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Glucose-Modified Low Density Lipoprotein Enhances Human Monocyte Chemotaxis

Cited by 30 publications

References 43 publications

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Impact of Antioxidants and HDL on Glycated LDL–Induced Generation of Fibrinolytic Regulators From Vascular Endothelial Cells

Platelet activation in type 2 diabetes mellitus

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