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1.  Examining the association between salivary cortisol levels and subclinical measures of atherosclerosis: the Multi-Ethnic Study of Atherosclerosis 
Psychoneuroendocrinology  2012;38(7):1036-1046.
To investigate the association between salivary cortisol and two markers of subclinical cardiovascular disease (CVD), coronary calcification (CAC), and ankle-brachial index (ABI).
Data from an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), the MESA Stress Study, were used to analyze associations of salivary cortisol data collected six times per day over three days with CAC and ABI. The authors used mixed models with repeat cortisol measures nested within persons to determine if specific features of the cortisol profile were associated with CAC and ABI.
total of 464 participants were included in the CAC analysis and 610 in the ABI analysis. The mean age of participants was 65.6 years. A 1-unit increase in log coronary calcium was associated with a 1.77% flatter early decline in cortisol (95% CI: 0.23, 3.34) among men and women combined. Among women low ABI was associated with a steeper early decline (−13.95% CI:−25.58, −3.39) and a marginally statistically significant flatter late decline (1.39% CI: −0.009, 2.81). The cortisol area under the curve and wake to bedtime slope were not associated with subclinical CVD.
This study provides weak support for the link between cortisol and measures of subclinical atherosclerosis. We found an association between some features of the diurnal cortisol profile and coronary calcification and ABI but associations were not consistent across subclinical measures. There are methodological challenges in detecting associations of cortisol measures at a point in time with health outcomes that develop over a lifetime. Studies of short-term mechanisms linking stress to physiological processes related to the development of early atherosclerosis may be more informative.
PMCID: PMC4020284  PMID: 23146655
salivary cortisol; ankle brachial index; coronary calcification; atherosclerosis; stress; cortisol awakening response; cortisol diurnal pattern; Multi-Ethnic Study of Atherosclerosis
3.  PPAR Agonist-Induced Reduction of Mcp1 in Atherosclerotic Plaques of Obese, Insulin-Resistant Mice Depends on Adiponectin-Induced Irak3 Expression 
PLoS ONE  2013;8(4):e62253.
Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate) and a PPARγ agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO) were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3) and decreased monocyte chemoattractant protein-1 (Mcp1) expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM), we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3−/− BMDM) resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3−/− BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.
PMCID: PMC3631170  PMID: 23620818
4.  Dietary Antioxidants and FEV1 Decline: the Health, Aging and Body Composition Study 
The European Respiratory Journal  2011;39(4):979-984.
Increased antioxidant defenses are hypothesized to decrease age- and smoking-related decline in lung function.
The relation of dietary antioxidants, smoking, and forced expiratory volume in the 1st second of effort (FEV1) was investigated in community-dwelling older adults in the Health, Aging, and Body Composition Study. 1,443 participants completed a food frequency questionnaire, self-reported smoking history, and had measurements of FEV1 at both baseline and after 4 years of follow-up. The association of dietary intake of nutrients and foods with antioxidant properties and rate of FEV1 decline was investigated using hierarchical linear regression models.
In continuing smokers (current smokers at both time points), higher vitamin C and higher intake of fruits and vegetables were associated with an 18 and 24 ml/year slower rate of FEV1 decline compared to lower intake (P<0.0001 and 0.003, respectively). In quitters (current smoker at study baseline, quit during follow-up), higher intake was associated with an attenuated rate of decline for each nutrient studied (p<0.003, all models). In non-smoking participants, there was little or no association of diet and rate of decline in FEV1.
The intake of nutrients with antioxidant properties may modulate lung function decline in older adults exposed to cigarette smoke.
PMCID: PMC3390780  PMID: 22005919
Aging; Dietary Intake; Lung Function Measurements; Oxidants/Antioxidants; Smoking and Health
5.  Hematopoietic Stem/Progenitor Cell Proliferation and Differentiation Is Differentially Regulated by High-Density and Low-Density Lipoproteins in Mice 
PLoS ONE  2012;7(11):e47286.
Hematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.
We hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.
Methods and Results
HSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr−/−) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G2M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr−/− mice. When BM Lin-Sca-1+cKit+ (i.e. “LSK”) cells were cultured in the presence of LDL in vitro we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin−) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM in vivo. HDL also reversed the LDL-induced monocyte and granulocyte differentiation in vitro.
Our data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.
PMCID: PMC3492382  PMID: 23144813
6.  CD36 Inhibitors Reduce Postprandial Hypertriglyceridemia and Protect against Diabetic Dyslipidemia and Atherosclerosis 
PLoS ONE  2012;7(5):e37633.
CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target.
PMCID: PMC3360746  PMID: 22662181
7.  Decrease of miR-146b-5p in Monocytes during Obesity Is Associated with Loss of the Anti-Inflammatory but Not Insulin Signaling Action of Adiponectin 
PLoS ONE  2012;7(2):e32794.
Low adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NFκB pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NFκB-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin.
miR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes.
miR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NFκB p65 DNA binding activity and TNFα. As a response IRAK3 and IRS1 protein increased. Mitochondrial and intracellular ROS production did not increase despite more inflammation. In addition, exposure of miR-146b-5p-depleted THP-1 monocytes to high levels of globular adiponectin resulted in an increased production of TNFα and intracellular ROS. Still, they did not lose their potential to increase IRAK3 and IRS1 protein and to decrease mitochondrial ROS.
miR-146b-5p, decreased in monocytes during obesity, is a major mediator of the anti-inflammatory action of globular adiponectin. It appears not to be involved in insulin signaling possibly by protective response of IRAK3 and lack of mitochondrial ROS production.
PMCID: PMC3290617  PMID: 22393448
8.  Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health Aging and Body Composition study 
Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2,985 subjects at baseline and after 7 years of follow-up.
We examined six T2D-related traits (T2D status, HbA1c, fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models.
In all subjects at baseline, oxLDL was positively associated with T2D (OR=1.3,95% CI:1.1–1.5), fasting glucose (β=0.03±0.006), HbA1c (β=0.02±0.004), fasting insulin (β=0.12±0.02), HOMA-IR (β=0.13±0.02) and negatively with adiponectin (β=−0.16±0.03), (all p<0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR=1.3, 95% CI:1.1–1.4) and 3 of its related traits (β=0.60±0.14 for BMI, β=0.74±0.17 for % body fat, β=0.29±0.06 for visceral fat;
all p<0.001). Furthermore, of 4 traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL were similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks.
Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.
PMCID: PMC3269343  PMID: 19780064
oxLDL; diabetes; oxidation; obesity
9.  Interleukin-1 Receptor-Associated Kinase-3 Is a Key Inhibitor of Inflammation in Obesity and Metabolic Syndrome 
PLoS ONE  2012;7(1):e30414.
Visceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders.
We searched a cluster of molecules that support interactions between these stress conditions in monocytes.
RNA expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells.
Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in IRAK3 and a decrease in SOD2, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells in vitro.
IRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention.
PMCID: PMC3260289  PMID: 22272346
10.  Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis 
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
11.  Stress in Obesity and Associated Metabolic and Cardiovascular Disorders 
Scientifica  2012;2012:205027.
Obesity has significant implications for healthcare, since it is a major risk factor for both type 2 diabetes and the metabolic syndrome. This syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is associated with high atherosclerotic cardiovascular risk, which can only partially be explained by its components. Therefore, to explain how obesity contributes to the development of metabolic and cardiovascular disorders, more and better insight is required into the effects of personal and environmental stress on disease processes. In this paper, we show that obesity is a chronic inflammatory disease, which has many molecular mechanisms in common with atherosclerosis. Furthermore, we focus on the role of oxidative stress associated with obesity in the development of the metabolic syndrome. We discuss how several stress conditions are related to inflammation and oxidative stress in association with obesity and its complications. We also emphasize the relation between stress conditions and the deregulation of epigenetic control mechanisms by means of microRNAs and show how this impairment further contributes to the development of obesity, closing the vicious circle. Finally, we discuss the limitations of current anti-inflammation and antioxidant therapy to treat obesity.
PMCID: PMC3820434  PMID: 24278677
12.  Differential Associations of Weight Dynamics With Coronary Artery Calcium Versus Common Carotid Artery Intima-Media Thickness 
American Journal of Epidemiology  2010;172(2):180-189.
Change and fluctuation in body mass index (BMI; weight (kg)/height (m)2) may be associated differently with coronary artery calcification (CAC) than with carotid artery intima-media thickness (IMT). The authors analyzed data on 2,243 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, initially aged 18–30 years, who were examined every 2–5 years over a 20-year period (1985–2006). BMI at year 0 was associated positively and linearly with CAC at year 20; however, the association of BMI with year 20 CAC became progressively U-shaped in subsequent examinations (years 10, 15, and 20). To understand the deepening U shape, the authors modeled year 20 BMI and its history using 3 indices: year 0 BMI, linear slope of BMI during 20 years, and BMI fluctuation during 20 years. In models including these 3 terms, year 0 BMI was associated positively with CAC, as was BMI fluctuation. However, adjusted odds ratios across quintiles of BMI slope (vs. the lowest quintile) were 0.7, 0.4, 0.5, and 0.4 (Ptrend < 0.01), suggesting higher risk of CAC with weight loss, plateauing after moderate weight gain. In contrast, IMT was associated positively with BMI at all examinations and with 20-year BMI slope and was unassociated with BMI fluctuation. Surprisingly, CAC risk was higher with BMI loss and lower with BMI gain, whereas associations with IMT were as expected.
PMCID: PMC2915485  PMID: 20519263
body mass index; body weight changes; carotid artery, common; coronary vessels; tunica intima; tunica media
13.  Oxidative Stress and Insulin Resistance 
Diabetes Care  2009;32(7):1302-1307.
Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults.
Biomarkers of oxidative stress (F2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000–2006.
There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P < 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000–2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F2Isop and HOMA-IR was not.
We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not.
PMCID: PMC2699736  PMID: 19389821
14.  Oxidized LDL and the metabolic syndrome 
Future lipidology  2008;3(6):637-649.
The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension and insulin resistance. It is associated with a high cardiovascular risk that can only partially be explained by its components. There is evidence that low-grade inflammation and high oxidative stress add to this risk. Oxidized LDL, a marker of lipoprotein-associated oxidative stress, is an emerging cardiovascular risk factor. In this review, we demonstrate that the metabolic syndrome exacerbates oxidized LDL in a feedback loop. We introduce molecular mechanisms underlying this loop. Finally, we demonstrate that weight loss and statin treatment lower metabolic syndrome factors associated with a reduction of oxidized LDL. The current data warrant further investigation into the role of lifestyle and therapeutic interventions that inhibit tissue-associated oxidation of LDL in the prevention of the metabolic syndrome.
PMCID: PMC2631666  PMID: 19802339
atherosclerosis; inflammation; metabolic syndrome; obesity; oxidative stress; oxidized LDL
15.  Association Between Circulating Oxidized Low-Density Lipoprotein and Incidence of the Metabolic Syndrome 
Experimental data support the hypothesis that oxidized low-density lipoprotein (LDL) is associated with the metabolic syndrome. However, this hypothesis has not been tested in humans.
To establish the relation of oxidized LDL with metabolic syndrome in the general community.
Design, Setting, and Participants
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a population-based, prospective, observational study. We studied 1889 participants who were between the ages of 18 and 30 years at the time of recruitment in 1985 and 1986 and living in 1 of 4 US metropolitan areas (41% African American; 56% women) and were seen both at year 15 (2000–2001, ages 33–45 years) and year 20 examinations (2005–2006).
Main Outcome Measure
The longitudinal association of oxidized LDL and incident metabolic syndrome. Oxidized LDL was measured with a monoclonal antibody-based enzyme-linked immunosorbent assay. The metabolic syndrome was defined according to the Adult Treatment Panel III of the National Cholesterol Education Program.
Incident metabolic syndrome was diagnosed at the year 20 follow-up in 12.9% (243 of 1889) of participants who did not have metabolic syndrome at the 15-year followup. The odds ratios (ORs) for incident metabolic syndrome after 5 years' follow-up and adjusted for age, sex, race, study center, cigarette smoking, body mass index, physical activity, and LDL cholesterol levels by quintiles of oxidized LDL were 2.1 (95% confidence interval [CI], 1.1–3.8) for the second quintile (55.4–69.1 U/L); 2.4 (95% CI, 1.3–4.3) for the third quintile (69.2–81.2 U/L); 2.8 (95% CI, 1.5–5.1) for the fourth quintile (81.3–97.3 U/L); and 3.5(95%CI, 1.9–6.6) for the fifth quintile (≥97.4 U/L). The adjusted ORs for incidence of dichotomous components of metabolic syndrome in the highest vs the lowest quintile of oxidized LDL were 2.1 (95% CI, 1.2–3.6) for abdominal obesity, 2.4 (95% CI, 1.5–3.8) for high fasting glucose, and 2.1 (95% CI, 1.1–4.0) for high triglycerides. Low-density lipoprotein cholesterol was not associated with incident metabolic syndrome or with any of its components in the fully adjusted model containing oxidized LDL.
Higher concentration of oxidized LDL was associated with increased incidence of metabolic syndrome overall, as well as its components of abdominal obesity, hyperglycemia, and hypertriglyceridemia.
PMCID: PMC2562739  PMID: 18492970

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