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Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations^1,2,3

¹ From the Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo

² Supported by the William G McGowan Charitable Fund.

³ Reprints not available. Address correspondence to P Dandona, Diabetes-Endocrinology Center of Western New York, State University of New York at Buffalo, 3 Gates Circle, Buffalo, NY 14209. E-mail: pdandona{at}kaleidahealth.org.

	ABSTRACT

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Background: Glucose intake has been shown to cause an increase in intranuclear nuclear factor-B and a decrease in inhibitor B that are consistent with a proinflammatory effect. We investigated the effect of glucose intake on 2 other proinflammatory transcription factors, activator protein 1 (AP-1) and early growth response 1 (Egr-1), and on the genes regulated by them, ie, the genes for matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and tissue factor (TF), respectively.

Objective: The objective of the study was to ascertain whether the intake of 75 g glucose induces an increase in AP-1, Egr-1, and the genes regulated by them.

Design: Eight healthy subjects were given 75 g glucose dissolved in 300 mL water to drink. Blood samples were collected before and 1, 2, and 3 h after glucose intake. Four weeks later, the same subjects were given 300 mL water sweetened with saccharine, and blood samples were collected at the same time points. Mononuclear cells (MNCs) were separated, and nuclear fractions were isolated.

Results: AP-1 and Egr-1 binding activities were significantly higher 1 and 2 h after glucose intake and then decreased toward the baseline by 3 h. The expression of MMP-2 and TF in MNC homogenates also was significantly higher at 2 and 3 h. Plasma concentrations of MMP-2 were significantly higher at 3 h, whereas those of MMP-9 were significantly higher at 1, 2, and 3 h. In addition, TF was significantly higher at 2 and 3 h. Intake of saccharine-sweetened water had no significant effect on the inflammatory mediators measured in this study.

Conclusion: Glucose induces proinflammatory changes, including increases in AP-1, Egr-1, MMPs, and TF, the factors that regulate processes that are potentially relevant to atherosclerotic plaque rupture and thrombosis.

Key Words: Glucose • inflammation • activator protein 1 • early growth response 1 • matrix metalloproteinase 2 • matrix metalloproteinase 9 • tissue factor

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We previously showed that glucose intake induces increases in reactive oxygen species generation by polymorphonuclear leukocytes and mononuclear cells (MNCs) and in lipid peroxidation in plasma (1). We also showed that glucose intake results in proinflammatory changes in MNCs, including an increase in intranuclear nuclear factor (NF)-B, a decrease in inhibitor B (IB), and an increase in p47^phox subunit, a key protein in NADPH oxidase (2).

We now hypothesize that 2 other proinflammatory transcription factors, activator protein 1 (AP-1) and early growth response 1 (Egr-1), increase after glucose intake. AP-1 regulates the transcription of matrix metalloproteinases (MMPs). The MMPs are a family of zinc-dependent proteases that are responsible for proteolytic degradation of specific extracellular matrix (ECM) components. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) hydrolyze the ECM and allow the spread of inflammation. Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors, including cytokines, growth factors, and cell contact to ECM. MMP gene expression occurs under tightly regulated mechanisms that lead to cell- and tissue-specific expression of the individual genes. Studies have reported a physical interaction between the transactivation domains of p65 and c-Jun or c-Fos and synergistic transactivation of multimerized AP-1 or B sites (3). Furthermore, MMP-2 action on ECM results in the cleavage of laminin-5 gamma 2 subunit at residue 587, which exposes a putative cryptic promigratory site that triggers cell motility (4). This action also allows neovascularization to occur under the influence of vascular endothelial growth factor (5), which is relevant to tissue repair mechanisms and to the pathogenesis of diabetic retinopathy.

Egr-1 is an 80- to 82-kDa inducible protein that is a prototype of the Egr gene family. Egr-1 is rapidly and transiently induced by a variety of extracellular stimuli related to hypoxia and vascular injury, growth factors, cytokines, and physical damage to blood vessels (6-9). It induces the transcription of platelet-derived growth factor A and B chains, basic-fibroblast growth factor, transforming growth factor-ß, macrophage–colony-stimulating factor, tumor necrosis factor , intercellular adhesion molecule 1, urokinase-type plasminogen activator, TF, plasminogen activator inhibitor 1, and MMPs (6, 9-16). Increased Egr-1 displaces Sp1 bound to the promoters of several genes, especially that of platelet-derived growth factor A chain (11); such an action may contribute to neointima formation through increased expression of platelet-derived growth factor.

Egr-1 also regulates TF expression in vascular smooth muscle cell, the endothelium and the monocytes (8, 17). The human TF promoter also contains binding sites for the transcription factors AP-1, c-Rel/p65, and Sp1 (18, 19). TF is a cell surface receptor for coagulation factor VII, and it initiates the extrinsic pathway of coagulation with the generation of thrombin (20, 21). Aberrant TF expression within the vasculature induced by hypoxia or hyperglycemia, or both, leads to thrombosis in patients with a variety of diseases, including septic shock, chronic unstable angina, atherosclerosis, and cancer.

In view of the above, we have now investigated the effect of glucose intake on AP-1 and Egr-1 binding activities in MNC nuclear extracts, the expression of MMP-2 and TF in MNC homogenates, and plasma concentrations of MMP-2 and TF.

	SUBJECTS AND METHODS

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Subjects
Eight subjects (5 men and 3 women) with an age range of 31–39 y, a weight range of 56.7–90.7 kg, and a mean body mass index (in kg/m²) of 25.6 ± 3.1 participated in the study. They were given 75 g glucose dissolved in 300 mL water (Glucola; Allegiance Healthcare Corporation, McGaw Park, IL) to drink within 5 min. Blood samples were obtained at 0, 1, 2, and 3 h. Four weeks later, the same subjects were given 300 mL water sweetened with saccharine (Cumberland Packing Corp, Brooklyn, NY) to be drunk within 5 min. Blood samples were again collected at the same time points. All subjects gave written informed consent to participate in the protocol, which was approved by the internal review board of the State University of New York at Buffalo, based at Millard Fillmore Hospital.

Mononuclear cell isolation
We carefully layered 3.5 mL of the anticoagulated blood sample over 3.5 mL of polymorphonuclear leukocytes isolation medium (Robbins Scientific Corp, Sunnyvale, CA). The sample was centrifuged at 450 x g for 30 min at 22 °C. At the end of the centrifugation, 2 bands separated out at the top of the red blood cell pellet. The top band consisted of MNCs, and the bottom band consisted of polymorphonuclear leukocytes. The MNC band was harvested and repeatedly washed with Hanks' balanced salt solution (HBSS; Gibco BRL, Grand Island, NY). This method provided MNC suspensions that are >95% pure. The purity was tested repeatedly to validate the method. Thereafter, random checks were made to ensure the purity of MNC preparation.

Activator protein 1 and early growth response 1 electrophoretic mobility shift assay
DNA-binding protein extracts were prepared from MNCs by the method described by Andrews et al (22). Briefly, MNC pellets were resuspended in 400 µL cold buffer A [10 mmol HEPES-KOH/L (pH 7.9), 1.5 mmol MgCl₂/L, 10 mmol KCl/L, 0.5 mmol dithiothreitol/L, 0.2 mmol phenylmethylsulphonylfluoride/L]. The cells were allowed to swell on ice for 10 min and then mixed by vortex for 10 s. Samples were centrifuged for 10 s at 14 000 x g and at 4 °C, and the supernatant fractions were discarded. The pellets were resuspended in 100 µL cold buffer B [20 mmol HEPES-KOH/L (pH 7.9), 25% glycerol, 420 mmol NaCl/L, 1.5 mmol MgCl₂/L, 0.2 mmol EDTA/L, 0.5 mmol dithiothreitol/L, 0.2 mmol phenylmethylsulphonylfluoride/L]. Samples were incubated on ice for 20 min for high-salt extraction and then centrifuged for 2 min at 14 000 x g and at 4 °C, and the supernatant fractions were collected. Total protein concentrations were determined by using a bicinchonic acid–based protein assay (Pierce, Rockland, IL). An electrophoretic mobility shift assay was performed by using a double-stranded oligonucleotide for AP-1 binding activity (Promega Inc, Madison, WI) containing the consensus sequence 5'-d(CGC TTG ATG AGT CAG CCG GAA)-3' and 3'-d(GCG AAC TAC TCA GTC GGC CTT)-5' and a double-stranded oligonucleotide for Egr-1 binding activity (Geneka Biotechnology Inc, Montreal, Canada) containing the consensus sequence 5'-GGATCCAGCGGGGGCGAGCGGGGGCGAACG-3' and 3'-CCTAGGTCGCCCCCGCTCGCCCCCGCTTGC-5'. The double-stranded oligonucleotide containing the consensus sequence for AP-1 or Egr-1 binding activity was radiolabeled with -³²P by T4 kinase. Then, 5 µg of the nuclear extract was mixed with the 5x incubation buffer [50 mmol Tris/L (pH 7.5), 500 mmol NaCl/L, 5 mmol dithiothreitol/L, 5 mmol EDTA/L, 20% glycerol, and 0.4 mg/mL sonicated salmon sperm], and the mixture was incubated at 4 °C for 15 min. Labeled oligonucleotide (60 000 cpm) was added, and the mixture was incubated at room temperature for 20 min. Samples were then applied to wells of 6% nondenaturing polyacrylamide gel. The gel was dried under vacuum and exposed to X-ray film. Densitometry was performed by using Bio-Rad molecular analyst software (version 1.4.1; Bio-Rad, Hercules, CA).

Measurements of plasma tissue factor and matrix metalloproteinases 2 and 9
We used enzyme-linked immunosorbent assay kits to assay plasma TF (American Diagnostica Inc, Greenwich, CT), plasma MMP-9 (R&D Systems, Minneapolis), and plasma MMP-2 (Amersham Pharmacia Biotech, Piscataway, NJ) concentrations.

Tissue factor and matrix metalloproteinase 2 Western blotting
Total protein concentrations were determined by using a bicinchonic acid–based protein assay (Pierce). We electrophoresed 40 µg MNC total homogenate on sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The proteins were transferred to polyvinylidene fluoride membrane, blocked for 1 h in 5% nonfat dry milk, and then incubated for 1 h with a monoclonal antibody to TF (Calbiochem, San Diego) or a polyclonal antibody to MMP-2 (Santa Cruz Inc, Santa Cruz, CA). Finally, the membrane was washed and developed with the use of West Femto chemiluminescence reagent (Pierce). Densitometry was performed by using Bio-Rad molecular analyst software (Bio-Rad).

Plasma insulin and glucose measurements
Insulin concentrations were determined with the use of an enzyme-linked immunosorbent assay kit (Diagnostic Systems Laboratories Inc, Webster, TX). Glucose concentrations were measured in whole blood by using a Hemocue glucose analyzer (Hemocue Inc, Mission Viejo, CA).

Statistical analysis
Statistical analysis was performed by using SIGMASTAT software (Jandel Scientific, San Rafael, CA). All data on AP-1 and Egr-1 binding activities, MMP-2, MMP-9, TF, and plasminogen activator inhibitor 1 were normalized to a baseline of 100% in view of the interindividual variability and are expressed accordingly as a percentage of the baseline. Analysis was carried out with one-factor repeated-measures analysis of variance by using Dunnett's test for comparisons against the baseline (0 h). Two-factor analysis of variance was used to evaluate the interaction between treatment (water or glucose) and time. The results are expressed as means ± SEMs.

	RESULTS

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Plasma glucose and insulin concentrations
Plasma glucose concentrations after glucose challenge increased from 93.5 ± 6.4 mg/dL at baseline to 128.6 ± 21.0 mg/dL at 1 h, 109.0 ± 20.1 mg/dL at 2 h, and 94.1 ± 10.1 mg/dL at 3 h (P < 0.05). Plasma insulin concentrations increased from 12.8 ± 4.2 µU/mL at baseline to 43.2 ± 7.5 µU/mL at 1 h, 17.6 ± 6.4 µU/mL at 2 h, and 11.7 ± 4.3 µU/mL at 3 h (P < 0.01). Water challenge did not change either glucose or insulin concentrations.

Early growth response 1 binding activity and total cellular early growth response 1 protein concentration
Intranuclear binding of Egr-1 to the consensus gene sequence described above increased after glucose challenge. This increase was significant at 1 h (179 ± 35% of the baseline) and 2 h (176 ± 29% of baseline; P < 0.05) after glucose challenge. Egr-1 binding activity decreased by 3 h after glucose challenge (Figure 1). Total cellular Egr-1 protein concentrations in MNC homogenates as seen on the Western blot did not change (Figure 2). Water intake did not change Egr-1 binding activity.

View larger version (32K): [in this window] [in a new window]   FIGURE 1.. A: Gel shift assay showing the relative binding after glucose challenge of early growth response 1 (Egr-1) to double-stranded oligonucleotide containing an Egr-1 DNA binding site. Lane 1: 0 h; lane 2: 1 h; lane 3: 2 h; lane 4: 3 h. B: Super-shift electrophoretic mobility shift assay was performed to confirm the specificity of Egr-1. This was accomplished by running recombinant Egr-1 protein in lane 1, super-shift with a monoclonal antibody (Ab) to Egr-1 in lane 2, nonspecific antibody (anti-p65 of nuclear factor-B) in lane 3, unlabeled competitor oligonucleotide for Egr-1 in lane 4, and nonspecific unlabeled oligonucleotide competitor in lane 5. C: Mean (± SEM) percentage change in Egr-1 binding activity after glucose or water intake. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

View larger version (25K): [in this window] [in a new window]   FIGURE 2.. A: A representative Western blot showing the quantity of early growth response 1 (Egr-1) protein in mononuclear cell (MNC) homogenates after glucose ingestion. Note that there was no significant change in Egr-1 protein concentrations in MNC homogenates. B: Mean (± SEM) percentage change in total Egr-1 protein content after glucose or water ingestion. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8.

Figure 3

Figure 4

View larger version (28K): [in this window] [in a new window]   FIGURE 3.. A: Western blot showing the relative expression of tissue factor (TF) in mononuclear cell (MNC) homogenates after glucose intake. Note that TF induction by glucose is observed at 1–2 h. B: Mean (± SEM) percentage change in total TF protein concentrations in MNC homogenates. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

View larger version (25K): [in this window] [in a new window]   FIGURE 4.. Mean (± SEM) percentage change in plasma tissue factor (TF) concentrations after intake of 75 g glucose or 300 mL water. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

Figure 5

View larger version (30K): [in this window] [in a new window]   FIGURE 5.. A: Gel shift assay showing the relative binding after glucose challenge of activator protein 1 (AP-1) to a double-stranded oligonucleotide containing an AP-1 DNA binding site. Band-shift assays were performed by using 5 µg mononuclear cell (MNC) nuclear extract for each time point. Lane 1: nuclear extract of HeLa cervical carcinoma cells; lane 2: radiolabeled AP-1 double-stranded oligonucleotide binding site without any nuclear extract; lane 3: 0 h; lane 4: 1 h; lane 5: 2 h; lane 6: 3 h. Neutralization assays with antibodies against c-Fos and c-Jun showed that the complex detected is a heterodimer of c-Fos and c-Jun. B: Mean (± SEM) percentage change after glucose or water challenge in AP-1 binding to a double-stranded oligonucleotide containing an AP-1 DNA binding site. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

Figure 6

Figure 7

Figure 8

View larger version (21K): [in this window] [in a new window]   FIGURE 6.. A: Western blot showing the relative expression of matrix metalloproteinase 2 (MMP-2) in mononuclear cell (MNC) homogenates. Note that the induction of MMP-2 after glucose challenge is similar to that of tissue factor (TF). B: Mean (± SEM) percentage change in total MMP-2 protein concentrations in MNC homogenates after glucose or water challenge. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett’s test). There was a significant interaction between treatment (water or glucose) and time (P < 0.005, two-factor ANOVA).

View larger version (32K): [in this window] [in a new window]   FIGURE 7.. Mean (± SEM) percentage change in total plasma matrix metalloproteinase 2 (MMP-2) concentrations after glucose or water intake. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

View larger version (27K): [in this window] [in a new window]   FIGURE 8.. Mean (± SEM) percentage change in total plasma matrix metalloproteinase 9 (MMP-9) concentrations after glucose or water challenge. All values were normalized to 100% for baseline, and the values were expressed as a percentage of baseline. n = 8. *Significantly different from baseline (0 h), P < 0.05 (one-factor repeated-measures ANOVA and Dunnett's test). There was a significant interaction between treatment (water or glucose) and time (P < 0.05, two-factor ANOVA).

	DISCUSSION

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Our data also show clearly that intranuclear Egr-1 binding activity increases significantly at 1 and 2 h after glucose intake and then declines by 3 h after glucose intake. However, the total expression of Egr-1 protein in the cell did not change after glucose intake. Clearly, therefore, this increase in Egr-1 binding to the TF gene promoter is independent of an increase in Egr-1 content, which suggests the possibility of a coactivator. Consistent with this increase in Egr-1 binding activity was the increase in TF protein expression in MNCs at 1 and 2 h after glucose challenge and that in TF concentration in plasma at 2 and 3 h after glucose challenge, which are suggestive of an increase in the biosynthesis and secretion of TF. TF is an activator of factor VII, which in turn activates factors IX and VIII; they cause the conversion of factor X into factor Xa, which converts prothrombin into thrombin. Thus, TF is ultimately a major determinant of the conversion of prothrombin to thrombin through the extrinsic pathway of coagulation. Thrombin is a potent activator of platelets and also converts fibrinogen to fibrin. Thrombin is a protease that is essential for both these actions, because the thrombin receptor on platelets is a protease-activated receptor requiring proteolysis, and the conversion of fibrinogen to fibrin also requires proteolysis. Thus, TF is potentially both proaggregatory and prothrombotic. These processes are cardinal to setting up intravascular thrombosis, which is secondary to a ruptured atherosclerotic plaque. Such a rupture exposes the foam cells in a plaque to intraluminal circulation, and, because foam cells express TF on their surface, plaque rupture triggers platelet aggregation and the formation of thrombin and, thus, thrombosis.

These data extend our previous observations that glucose and mixed macronutrient intakes result in oxidative stress and proinflammatory changes, including an increase in intranuclear NF-B and reactive oxygen species generation and a decrease in IB (30-32). The data presented here show that carbohydrate intake may also result in a state that promotes MMP and TF secretion. Through these actions, carbohydrate intake may promote endothelial damage, plaque thinning, plaque rupture, and an increase in thrombotic factors. This possibility suggests that very large meals may result in acute thrombotic episodes in patients with preexistent atherosclerosis. There are data to show that exercise-induced angina thresholds are lower in the postprandial state than in the fasting state (33), but the association of large meals with acute myocardial infarction remains to be shown.

It is important to emphasize that these effects of glucose intake were observed after 75 g glucose intake in healthy subjects, and the maximal concentration achieved was 128 mg/dL. This is not in the hyperglycemic range, and thus the effect is not a function of hyperglycemia. It should also be noted that these effects are not due to insulin that is secreted in response to glucose intake, because insulin actually exerts an anti-inflammatory effect and suppresses NF-B (2), AP-1 (34), Egr-1 (35), and MMP-2, MMP-9, TF, plasminogen activator inhibitor 1, and vascular endothelial growth factor (2, 36), as previously shown by us. Insulin also suppresses C-reactive protein and serum amyloid A in patients with acute myocardial infarction (37).

The proinflammatory effect of glucose and the anti-inflammatory effect of insulin have potentially been shown to be of relevance in patients treated in intensive care units. In a series of 1500 patients, those whose glucose concentrations were maintained between 80 and 120 mg/dL had markedly less mortality and morbidity than did those with higher blood glucose concentrations (38). Similar beneficial effects of lowering blood glucose concentrations through low-dose insulin infusion were observed in patients with acute myocardial infarction in coronary care units (39, 40). It is possible that glucose-induced MMP-2 and TF increases are relevant to further plaque rupture and thrombosis.

We conclude that glucose intake results in an increase in the activity of the pro-inflammatory transcription factors, AP-1 and Egr-1, in the nucleus with concomitant increases in the expression of MMP-2 and TF in MNCs. There were simultaneous increases in plasma concentrations of MMP-2 and TF. These observations are relevant to macronutrient intakes and thrombogenesis.

	ACKNOWLEDGMENTS

 
The authors thank Ajay Chaudhuri for valuable critical comments.

AA, PM, AB, and PD were responsible for planning the study; AA, HG, PM, and TS conducted the study; AA, HG, AB, and PD analyzed the results; and AA, AB, and PD were responsible for writing the report. None of the authors had a personal or financial conflict of interest.

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