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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2438
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6454-6459
Copyright © 2005 by The Endocrine Society

Circulating Levels of Oxidative Stress Markers and Endothelial Adhesion Molecules in Men with Abdominal Obesity

Charles Couillard, Guillaume Ruel, W. Roodly Archer, Sonia Pomerleau, Jean Bergeron, Patrick Couture, Benoit Lamarche and Nathalie Bergeron

Institute of Nutraceuticals and Functional Foods (C.C., G.R., W.R.A., S.P., P.C., B.L.) and Department of Food Sciences and Nutrition (C.C., B.L., N.B.), Laval University, Québec, Canada G1K 7P4; and the Lipid Research Center, Laval University Medical Center (J.B., P.C.), Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Charles Couillard, Ph.D., Assistant Professor, Institute of Nutraceuticals and Functional Foods, 2440 Boulevard Hochelaga, Room 2742, Laval University, Sainte-Foy (Québec), Canada G1K 7P4. E-mail: charles.couillard{at}inaf.ulaval.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: It has been suggested that oxidative stress and endothelial dysfunction could play a role in the higher cardiovascular disease risk noted in the abdominally obese population.

Objective: The objective of this study was to describe the associations between abdominal fat accumulation, oxidative stress, and endothelial dysfunction in men.

Design: A complete physical and metabolic profile was assessed in a group of 56 men covering a wide range of adiposity and plasma oxidized low-density lipoprotein (OxLDL), and soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin, and C-reactive protein concentrations were determined.

Results: We found that abdominal visceral adipose tissue was positively associated with plasma OxLDL (r = 0.52; P < 0.0001) and C-reactive protein (r = 0.60; P < 0.0001) concentrations. We also found significant associations between plasma E-selectin levels and hyperinsulinemia (r = 0.39; P < 0.005) as well as with the homeostasis model assessment index of insulin resistance (r = 0.42; P < 0.005).

Conclusions: Our study showed that plasma OxLDL levels and low-grade systemic inflammation are increased in men with a high visceral adipose tissue accumulation. Furthermore, our results support the notion that insulin resistance is associated with endothelial activation. Overall, our observations give us further insights on the increased cardiovascular disease risk frequently noted among viscerally obese, insulin-resistant individuals.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CARDIOVASCULAR DISEASE (CVD) is the leading cause of death in North America (1), and numerous population-based studies have shown that an elevated plasma low-density lipoprotein (LDL) cholesterol level is a strong predictor of such a pathology (2). Although the physiological mechanisms by which LDL cholesterol increases the risk of developing CVD are still under investigation, the atherosclerotic process resulting from the accumulation of cholesterol within the artery wall is well documented. It has been shown that oxidized LDL (OxLDL) particles promote macrophage foam cell formation, which is the predominant cell type in the earliest atherosclerotic lesions known as fatty streaks (2). Moreover, the presence of OxLDL in atherosclerotic lesions suggests that lipoprotein oxidation plays a causative role in early atherogenesis. In this regard, there is now a large body of evidence indicating that OxLDLs are involved in several steps of atherosclerosis, e.g. endothelial injury, monocyte chemotaxis, inflammation, perturbation of vascular tone, synthesis of growth factors, vascular remodeling, and autoantibody formation (3, 4).

Vascular endothelial cells have long been considered as inactive and acting as only a semipermanent barrier between blood and tissues (5). However, there is now increasing evidence supporting the role of the vascular endothelium in maintaining homeostasis in humans. For instance, in response to their activation, endothelial cells express a large selection of molecules, including adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which are involved in the modulation of leukocyte recruitment and platelet adhesion during thrombosis and inflammation (6). It is also well established that chronic activation of the endothelium, often referred to as endothelial dysfunction, plays an integral role in the development of atherosclerosis and CVD (2). Endothelial dysfunction can be triggered by inflammation stimuli that include free radicals and cytokines. LDL oxidation is also associated with an increase in the expression of adhesion molecules at the endothelium surface, which facilitate the infiltration of monocytes into the subendothelial space (2). In healthy individuals, activation of endothelial cells is temporary, and its duration will be affected by the intensity of the inflammatory stimulus. However, high concentrations of soluble (s) ICAM-1 and VCAM-1 have been reported in plasma of type 2 diabetes (7, 8, 9) and obese (10, 11) individuals as well as in CVD patients (12), which are all conditions associated with low-grade systemic inflammation.

Abdominal obesity, especially high visceral fat accumulation, is associated with a dyslipidemic profile that includes high plasma triglyceride (TG) and apolipoprotein (apo) B levels, low HDL cholesterol concentrations, as well as an increased proportion of small, dense LDL particles (13, 14). These peculiar lipoprotein-lipid disturbances increase the likelihood for the oxidative modification of lipoproteins (15). The present study was therefore undertaken to further investigate the relationships between abdominal fat accumulation, oxidative stress, endothelial activation, and inflammation in men.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fifty-six healthy sedentary men (mean age ± SD, 40 ± 12 yr) were recruited through the media in the Québec metropolitan area and selected to cover a wide range of body fatness values. Exclusion criteria included endocrine, cardiovascular, hepatic, and renal disorders; use of medication known to affect lipid metabolism; smoking; and significant changes in body weight within the year before the study. Individuals reporting the use of antiinflammatory medications or a proinflammatory condition (infections, trauma, etc.), as well as those with excessive alcohol intake and unusual dietary habits were also excluded from the study. Each participant signed a consent form approved by the Medical Ethics Committee of Laval University.

Anthropometry, body composition, and fat distribution

Body weight, height, and waist and hip circumferences were measured following standardized procedures (16), and the body mass index (BMI) as well as waist-to-hip ratio (WHR) were calculated. Visceral and sc adipose tissue (AT) areas were assessed by computed tomography using previously described procedures (17).

Plasma lipid, lipoprotein, and apo measurements

Blood samples were obtained in the morning after a 12-hr overnight fast. Cholesterol and TG levels were determined by enzymatic methods using the Technicon RA-500 analyzer (Bayer Corporation. Inc., Tarrytown, NY), as previously described (18). Plasma very LDLs (density < 1.006 g/ml) were isolated by ultracentrifugation, and the HDL fraction was obtained after precipitation of LDLs in the infranatant (density > 1.006 g/ml) with heparin and MnCl2 (19). The cholesterol and TG contents of the infranatant fraction were measured before and after the precipitation step. apoB levels were measured by nephelometry on a Behring BN-100 nephelometer (Dade Behring, Mississauga, Ontario, Canada). Lyophilized serum standards for apo measurements were prepared at our laboratory and calibrated with reference standards obtained from the Centers for Disease Control (Atlanta, GA). Distinct subpopulations of LDL particles were separated in whole plasma using nondenaturing 2–16% gradient gel electrophoresis as described previously (20). LDL peak particle diameter (LDL-PPD) was identified as the most important subclass of LDL in each individual and was calculated from calibration curves using plasma standards of known diameter. The coefficient of variation of the calculated particle diameters was estimated to be 2%.

Oxidative stress, endothelial function, and inflammation markers

Plasma 8-iso-prostaglandin F2{alpha} (8-iso-PGF2{alpha}) concentrations (n = 46; Assay Designs, Inc., Ann Arbor, MI) and OxLDL concentrations (Alpco Diagnostics, Windham, NH) were measured by immunoassay using commercial kits. Soluble ICAM-1, VCAM-1, and E-selectin levels were also measured in fasting plasma by ELISA specific to the human forms of these adhesion molecules (R&D Systems, Inc., Minneapolis, MN). All these measurements were done on the same day, and the intraassay coefficients of variation of the different techniques are no greater than 5%. Measurement of C-reactive protein (CRP) levels was obtained by nephelometry with a highly sensitive immunoassay that used a monoclonal antibody coated to polystyrene particles (high-sensitivity CRP). The interassay coefficient of variation for the CRP measurement was less than 4% (21).

Insulin, glucose, and homeostasis model assessment index of insulin resistance (HOMA-IR)

Plasma glucose concentrations were determined with a glucose oxidase assay from Sigma (St. Louis, MO) (22), and insulin levels were also measured in plasma using a commercial double-antibody RIA (Linco Research, St. Louis, MO) that shows little cross-reactivity (< 0.02%) with proinsulin (23). The HOMA-IR was calculated (24).

Statistical procedures

Spearman’s correlation coefficients were calculated to test for associations between the different variables. When needed, values were log10 transformed for analysis, but for practical reasons raw data are presented in tables and figures. Differences between means were tested by ANOVA with Bonferroni correction for multiple comparisons. We also used a second arbitrary nominal threshold P value of < 0.01 for significance of correlations to decrease the possibility of false positives (type I error) and because the Bonferroni correction (P value of 0.05/number of tests) would have been overly conservative. In the different tables and figures, borderline significance is defined as a P value between 0.01 and 0.05 and is shown in parentheses. All analyses were conducted using the SAS statistical package (version 8.2; SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the physical and metabolic characteristics of the subjects. As a group, men were obese (BMI > 30 kg/m2), with a relatively important abdominal fat accumulation as revealed by a waist circumference of 102 cm. This value was well above the cutpoint of 90 cm suggested to identify subjects most susceptible of displaying the metabolic disturbances of abdominal obesity (14) and equal to the threshold value used by the National Cholesterol Education Program (25) to determine the presence of the metabolic syndrome. Accordingly, subjects had slightly elevated plasma TGs and decreased HDL cholesterol concentrations. Although, no reference values have been established for circulating inflammatory, lipoprotein-lipid oxidation, and endothelial activation markers, we noticed a large range of values for CRP, OxLDL, 8-iso-PGF2{alpha}, sICAM-1, sVCAM-1, and E-selectin, which is supportive of the metabolic heterogeneity of the group of men under study.


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  		TABLE 1. Characteristics of the subjects

 
Associations between circulating plasma oxidative stress markers, adhesion molecules, obesity, and abdominal fat distribution are shown in Table 2Go. We found that visceral AT accumulation was positively associated to plasma OxLDL (r = 0.52; P < 0.005) and CRP (r = 0.60; P < 0.005) concentrations. A dyslipidemic profile including high cholesterol, TG, and apoB concentrations (Table 2Go) as well as the presence of small, dense LDL particles was associated with elevated plasma OxLDL levels (Fig. 1Go). Similar relationships were found between lipoprotein-lipid alterations, with the exception of small dense LDL, and plasma CRP concentrations. Plasma E-selectin concentrations tended (P between 0.01 and 0.05) to be higher with increasing plasma cholesterol, TG, and apoB levels but were significantly associated with hyperinsulinemia (r = 0.39; P < 0.005) and insulin resistance assessed by the HOMA-IR (r = 0.42; P < 0.005). Plasma sVCAM-1 and sICAM-1 concentrations did not appear to be affected by a dyslipidemic condition. Furthermore, we found no significant association between adiposity or metabolic profile variables and plasma 8-iso-PGF2{alpha} concentrations. However, when overweight subjects (BMI, 25–30 kg/m2) were eliminated from the group, we found that plasma 8-iso-PGF2{alpha} levels tended to be higher in obese (BMI ≥ 30 kg/m2; n = 24) vs. nonobese (BMI ≤ 25 kg/m2; n = 5) individuals (1.50 ± 0.71 vs. 0.86 ± 0.37 ng/ml, respectively; P = 0.0457).


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  		TABLE 2. Spearman correlation coefficients between plasma oxidative stress marker and adhesion molecule levels, adiposity, fat distribution, and the metabolic profile

 


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  		FIG. 1. Associations between LDL-PPD and plasma OxLDL concentrations in men.

 
We found that circulating OxLDL levels were not significantly correlated to adhesion molecules, although a borderline association was found with plasma sICAM-1 concentrations (r = 0.28; P = 0.0354). On the other hand, plasma 8-iso-PGF2{alpha} levels were significantly associated with plasma E-selectin (r = 0.42; P < 0.005) but showed no relationship with either circulating sICAM-1 or sVCAM-1 levels.

We conducted multiple regression analyses to quantify the independent contributions of different adiposity and metabolic variables to the variations in plasma OxLDL, sICAM-1, sVCAM-1 and E-selectin concentrations (Table 3Go). We found that circulating OxLDL concentrations were best explained by visceral AT accumulation (R2 = 0.223; P < 0.0005) while circulating sICAM-1 were predicted by E-selectin (R2 = 0.247; P < 0.0001).


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  		TABLE 3. Regression analyses showing the independent contributions of physical and metabolic characteristics to the variation of plasma OxLDL, sICAM-1, sVCAM-1, and E-selectin concentrations

 
Finally, to investigate further the relationship between visceral obesity, plasma OxLDL levels, and inflammation, we compared plasma CRP levels in men divided on the basis of plasma OxLDL levels (50th percentile, low vs. high) but with either low (< 130 cm2) or high (≥ 130 cm2) visceral AT accumulation (Fig. 2Go). We found a borderline significant effect of OxLDL on plasma CRP concentrations (P = 0.05). On the other hand, visceral obesity was associated with high plasma CRP levels (P < 0.005). There was no significant interaction effect of visceral obesity*OxLDL on circulating CRP concentrations.



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  		FIG. 2. Plasma CRP levels in men with low (< 130 cm2) vs. high (≥ 130 cm2) abdominal visceral AT accumulation in the absence (black bars) or presence (white bars) of elevated OxLDL (50th percentile = 39.2 U/liter) concentrations. Values are means ± SEM. Effect of visceral AT, P = 0.003; effect of OxLDL, P = 0.05; interaction, not significant.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The dysmetabolic condition of abdominal obesity is now well documented and includes hypertriglyceridemia, low HDL cholesterol, hyperinsulinemia, insulin resistance, and systemic inflammation (26, 27). The present study extends the metabolic deterioration of abdominally obese, insulin-resistant individuals to increased lipoprotein oxidation and vascular endothelial activation because we found significant associations between visceral fat accumulation and circulating levels of OxLDL as well as a positive relationship between hyperinsulinemia/insulin resistance and plasma E-selectin concentrations. Our observations are also in line with a recent study showing that plasma OxLDL levels were increased (28) and insulin resistance was the principal determinant of endothelial dysfunction (29) in individuals with the metabolic syndrome.

Oxidative stress is a term used to define the imbalance in the rate at which the intracellular content of free radicals, produced through a number of cellular events (30), increases relative to the capacity of the cell to dispose of these oxidants. When not neutralized, these free radicals have the capacity to alter the integrity of numerous molecules such as proteins and DNA (31). Lipids can also be the target of free radical attacks, and measures of plasma lipid peroxidation and lipoprotein oxidation are often used as markers of oxidative stress. Increased lipid peroxidation is noted in insulin resistance (32) as well as in individuals with impaired postprandial lipid handling (33). However, whether oxidative stress is a cause and/or consequence of these conditions is still under investigation. Furthermore, increased lipid peroxidation has been reported in obese men and women (34, 35). Our results tend to support these previous observations because we found higher plasma 8-iso-PGF2{alpha} concentrations in obese (BMI ≥ 30 kg/m2) compared with nonobese (BMI ≤ 25 kg/m2) men. It would have been interesting to consider the association between plasma 8-iso-PGF2{alpha} concentrations and features of the metabolic syndrome with regard to arachidonate intake or plasma levels because this fatty acid is part of the synthesis of prostaglandins. Unfortunately, this information was not available to us. On the other hand, obesity and abdominal visceral AT accumulation especially were found to be associated with increased plasma OxLDL levels.

Hypertriglyceridemia is a common feature of individuals with excessive visceral AT accumulation. These high plasma TG levels contribute to increase the transfer, through the action of the cholesterol ester transfer protein, of TG from VLDL to LDL and HDL particles in exchange for cholesterol esters from LDL, ultimately leading to the TG enrichment of LDL and HDL (36, 37). Such TG-rich LDL particles are an adequate substrate for hepatic lipase generating atherogenic small, dense LDL particles (38). Because of their size, these particles have a reduced affinity for hepatic LDL receptors and thus have a longer residence time in plasma (39). This increases the likelihood of interaction with free radicals and thus the probability of the particles to be oxidized. In fact, the differences in the distribution of buoyant vs. dense LDL particles has been previously found to be an important factor in the explanation of the increased susceptibility of LDL to oxidation (15). Results from the present study support such a susceptibility of small dense LDL particles to oxidation because we found a significant inverse relationship between plasma OxLDL concentrations and LDL-PPD. It has been suggested that a greater unsaturated fatty acid content compared with native LDL (40), physical characteristics similar to other LDL species enriched in oxysterols (41), and modifications of the lipid content of LDL, i.e. loss of antioxidants transported by LDL during particle remodeling (15, 42, 43), may explain the increased susceptibility to oxidation and proatherogenic potential of small dense LDL particles. Unfortunately, composition of LDL particles was not assessed in the present study, and its role in the apparent greater susceptibility of small dense LDL particles in the context of visceral obesity could not be investigated.

Small, dense LDL particles are also more likely to filtrate through the endothelium of blood vessels, to be oxidized, and to activate endothelial cells, which will promote an immune response leading to the formation of lipid-laden macrophages. Indeed, in response to inflammatory stimuli, endothelial cells produce adhesion molecules like VCAM-1, ICAM-1, and E-selectin that will further facilitate macrophage migration from the blood into the intima. Concordant with that process, plasma OxLDL levels have been positively associated to circulating sICAM-1 concentrations (44). In the present study, we found that plasma sICAM-1 concentrations tended to be increased in subjects with high OxLDL. On the other hand, it has been reported that obesity and more especially visceral AT accumulation are associated with alteration of the endothelial function (45). Insulin resistance, a condition often reported in viscerally obese individuals, has also been associated with high plasma sICAM-1 and E-selectin concentrations in Pima Indians (11), and circulating adhesion molecule levels have been reported to be good correlates of impaired vascular reactivity (46). Although visceral AT accumulation only showed borderline significant associations with plasma sVCAM-1 and E-selectin concentrations, our results are supportive to some extent of the relationship between insulin resistance and endothelial activation/dysfunction (29) because we found significant associations between fasting insulin as well as the HOMA-IR and plasma E-selectin levels.

In recent years, circulating levels of CRP have been clearly identified as a powerful independent risk factor for CVD (47, 48). In the present study, we further investigated the relationship between oxidative stress, visceral obesity, and low-grade inflammation by comparing plasma CRP levels in men showing either low vs. high levels of visceral AT in the presence or absence of high circulating OxLDL concentrations. Results of the multivariate analyses revealed a significant effect of visceral obesity on plasma CRP levels but a borderline significant effect of plasma OxLDL levels on circulating CRP concentrations. Our results certainly demonstrate the close relationship between visceral obesity and low-grade systemic inflammation and also suggest, to a certain extent, that the presence of varying plasma OxLDL concentrations could be implicated in the heterogeneity of plasma CRP levels reported among the viscerally obese population, although the latter assumption needs to be investigated further.

In summary, our results show that plasma OxLDL levels are increased in abdominally obese men with a high visceral AT accumulation. Furthermore, our results support the notion that insulin resistance is associated with endothelial activation, which gives us further insights on the deleterious impact of visceral obesity and insulin resistance with regard to CVD risk. Because the present study is mainly descriptive, further studies are clearly needed to better understand the extent of the respective roles, if any, of OxLDL, endothelial dysfunction, and inflammation in the increased CVD risk noted among abdominally obese, insulin-resistant individuals.


   Acknowledgments
 
The authors express their gratitude to the participants for their invaluable contribution and to Louise Corneau for her dedicated work.


   Footnotes
 
This study was made possible through grants from the Canadian Institutes of Health Research and the Fonds de la Recherche en Santé du Québec. C.C. and P.C. are research scholars from the Fonds de la Recherche en Santé du Québéc. C.C. is also supported by the Chair in Nutrition, Lipidology, and Cardiovascular Disease funded by Pfizer Canada and Provigo. B.L. holds a Canada Research Chair in Nutrition, Functional Foods, and Cardiovascular Health.

First Published Online September 27, 2005

Abbreviations: AT, Adipose tissue; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; HOMA-IR, homeostasis model assessment index of insulin resistance; ICAM-1, intercellular adhesion molecule-1; 8-iso-PGF2{alpha}, 8-iso-prostaglandin F2{alpha}; LDL, low-density lipoprotein; OxLDL, oxidized LDL; PPD, peak particle diameter; s, soluble; TG, triglyceride; VCAM-1, vascular cell adhesion molecule-1.

Received December 13, 2004.

Accepted September 15, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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