Cytokines, Modified Lipoproteins, and Arteriosclerosis in Diabetes

Lopes‐Virella, Maria F.; Virella, Gabriel

doi:10.2337/diab.45.3.s40

Cited by 62 publications

(29 citation statements)

References 33 publications

(46 reference statements)

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“…Cellular responses to elevated extracellular glucose are thought to contribute to the development of diabetic complications (19), including severe periodontitis (15), although the precise mechanism remains elusive. In the present study, we demonstrated for the first time that chronic HG exposure significantly increased gp130 mRNA as well as its protein expression in HGFs (Figs.…”

Section: Discussionmentioning

confidence: 99%

High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts

Omori

Naruishi

Nishimura

et al. 2004

Journal of Biological Chemistry

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Diabetic patients are susceptible to severe inflammatory periodontitis manifesting as swollen gingiva with bleeding, but the underlying mechanism is not well understood. Our purpose was to determine the effect of a high glucose (HG) condition on the interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-induced activation of signaling and vascular endothelial growth factor (VEGF) expression in human gingival fibroblasts (HGFs). In this study, HGFs were cultured for at least two passages under a normal glucose (NG; 5.5 mM) condition or high glucose (25 mM) condition. Importantly, the HG condition significantly induced expression of gp130 mRNA in HGFs compared with levels in control cells. Consistent with the expression of its mRNA, the HG condition also increased the expression of gp130 protein, and phosphorylation of the tyrosine residue by gp130 was enhanced significantly by IL-6/sIL-6R stimulation. Furthermore, the HG condition enhanced the IL-6/sIL-6R-induced phosphorylation of p44/42 MAPK and led to subsequent activation of CCAAT/enhancer binding protein in nuclei. In contrast, there was no significant difference in phosphorylation of JNK between the HG and NG condition. Interestingly, HGFs increased IL-6/sIL-6R-induced VEGF165 mRNA expression and VEGF165 secretion under the HG condition compared with levels under the NG condition. In contrast, the induction of VEGF165 secretion was partially inhibited by PD98059 (selective p44/42 MAPK inhibitor) under the HG condition. In addition, the VEGF165 secretion was completely inhibited by the combination of PD98059 and SP600125 (JNK inhibitor). Our findings suggest that the HG condition indirectly increases VEGF expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in HGFs. Thus, elevated VEGF secretion in HGFs under the HG condition may play a role in the development of the severe periodontitis observed in diabetic patients.

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Section: Discussionmentioning

confidence: 99%

High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts

Omori

Naruishi

Nishimura

et al. 2004

Journal of Biological Chemistry

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“…Although the functional consequences of such antibodies are not completely clear, is has been suggested that such antibodies enhance LDL cholesterol turnover via opsonization, promote intracellular accumulation of cholesteryl esters in macrophages and fibroblasts (1), and promote cytokine (interleukin ␤ and tumor necrosis factor alpha) production by macrophages (25). Thus, these antibodies could have either a protective or proinflammatory function.…”

Section: Vol 69 2001mentioning

confidence: 99%

Phosphorylcholine-Dependent Cross-Reactivity between Dental Plaque Bacteria and Oxidized Low-Density Lipoproteins

et al. 2001

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Antibodies reactive with phosphorylcholine (PC) are ubiquitous in human sera, but the antigens stimulating their production and their function are not clear. Previous studies have shown that a significant proportion of dental plaque bacteria contain PC as determined by reactivity with PC-specific mouse myeloma proteins and monoclonal antibodies. Additionally, serum antibody concentrations of immunoglobulin (IgG) G anti-PC are higher in sera of individuals who have experienced periodontal attachment loss than those who are periodontally healthy. These data implicate the oral microflora as a source of antigen-stimulating anti-PC responses. Recent data also indicate that antibodies with specificity for PC are elevated in ApoE-deficient mice, a model for studies of athersclerosis, and that such antibodies bound oxidized low-density lipoproteins (LDL) (oxLDL) in atherosclerotic plaques. These data prompted the hypothesis that human anti-PC could bind to both oral bacteria and human oxLDL, and that these antigens are cross-reactive. We therefore examined the ability of human anti-PC to bind to PC-bearing strains of oral bacteria using enzyme-linked immunosorbent inhibition assays and by assessment of direct binding of affinity-purified human anti-PC to PC-bearing Actinobacillus actinomycetemcomitans. Our results indicated that PC-bearing strains of Streptococcus oralis, Streptococcus sanguis, Haemophilus aphrophilus, Actinomyces naeslundii, Fusobacterium nucleatum, and A. actinomycetemcomitans, as well as a strain of Streptococcus pneumoniae, absorbed up to 80% of anti-PC IgG antibody from human sera. Furthermore, purified anti-PC bound to a PC-bearing strain of A. actinomycetemcomitans but only poorly to a PC-negative strain. OxLDL also absorbed anti-PC from human sera, and oxLDL but not LDL reacted with up to 80% of the anti-PC in human sera. Furthermore, purified anti-PC bound directly to oxLDL but not to LDL. The data indicate that PC-containing antigens on a variety of common oral bacteria are cross-reactive with neoantigens expressed in oxLDL. We propose that PC-bearing dental plaque microorganisms may induce an antibody response to PC that could influence the inflammatory response associated with atherosclerosis.

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“…These anti bodies have been found in plasma and atheroscle rotic plaque in diabetic patients (39). It has been con firmed that serum of type I diabetic patients contains oxidized LDL antibodies as well as oxidized LDL immunocomplexes (antigen-antibody) (40). The pre - sence of such immunocomplexes may be considered a risk factor for macrovascular diseases in these patients.…”

Section: Action Of Age Products Through Receptor-non-mediated Mechanismsmentioning

confidence: 99%

The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes

Čolak¹,

Majkić-Singh²

2009

Journal of Medical Biochemistry

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The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes Oxidative stress is the result of increased production of free radicals, which impair the cell function and cause many pathological conditions and diseases. The development of diabetes, its course and complications are closely associated with an imbalance in pro-antioxidative cell state and change of redox potential. Prolonged exposure to hyperglycemia is currently considered the major factor of the pathogenesis of atherosclerosis in diabetes. Atherosclerosis is the cause of about 80% of mortality in diabetics, and over 75% of all hospitalized diabetic patients have associated cardiovascular complications. Hyperglycemia induces different vascular tissue damage at the cellular level, which potentially accelerates the atherosclerotic processes. The most significant mechanisms responsible for acceleration of atherosclerotic processes in diabetic patients are: a) non-enzymatic protein and lipid glycosylation which interferes with normal function, in the way that it deranges molecular conformation, impairs enzymatic function, reduces the capacity of breakdown and interferes with recognition of protein structures by receptors; b) interaction of glycosylated proteins with their receptors resulting in induction of oxidative stress and pro-inflammatory reactions; c) polyol pathway; d) hexosamine pathway and e) activation of protein kinase C and impaired growth factor expression.

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Cytokines, Modified Lipoproteins, and Arteriosclerosis in Diabetes

Cited by 62 publications

References 33 publications

High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts

High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts

Phosphorylcholine-Dependent Cross-Reactivity between Dental Plaque Bacteria and Oxidized Low-Density Lipoproteins

The effect of Hyperglycemia and Oxidative Stress on the Development and Progress of Vascular Complications in Type 2 Diabetes

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