In a biracial, community-based population from metropolitan Atlanta, we found that African Americans had significantly lower levels of plasma glutathione and a more oxidized Eh glutathione compared with whites, even after adjustment for traditional CVD risk factors and inflammation. Furthermore, the prevalence of metabolic syndrome was similar in African Americans and whites, but did not account for differences in levels of oxidative stress. Thus, even among participants who would traditionally be considered at lower risk because they did not meet criteria for metabolic syndrome, African Americans had lower levels of glutathione and a more oxidized Eh glutathione. Classification according to conventional risk scores may therefore underestimate racial disparities in CVD risk that could potentially be related to the observed differences in oxidative stress.
Previously, nonthiol markers have been measured in studies examining racial differences in oxidative stress. Among various lipid-based measures of oxidative stress, African-American race was associated with increased levels of lipid hydroperoxides in diabetics, oxidized LDL-C, and plasma isoprostanes after lipid infusion, although no baseline differences were observed.26–28
However, there are few other studies that have examined racial differences in aminothiol markers of oxidative stress. In selected small populations, plasma levels of glutathione were lower in healthy African-American adults compared to whites.29
Thus, ours is the largest population-based study to examine racial differences in aminothiol markers of oxidative stress to date.
The relationship between markers of inflammation and oxidative stress is also of considerable interest in regard to racial disparities in CVD. Isoprostanes and lipid hydroperoxides correlate with hsCRP levels, providing support for the interconnection between inflammation and oxidative stress in the pathogenesis of atherosclerosis.30,31
Although modifiable risk factors such as obesity and type 2 diabetes are major determinants of hsCRP levels, nonmodifiable risk factors such as African-American race and female gender have also been associated with elevated hsCRP levels.6,32
We have confirmed these findings in our cohort. In multivariable models, we also found that glutathione was an independent correlate of hsCRP levels, whereas CRP was not a predictor of glutathione levels. Thus, our data suggest that oxidative stress may contribute to increases in inflammation, and that both of these atherogenic pathways are influenced by race and gender.
Our previous studies in selected smaller cohorts have demonstrated increased levels of aminothiol markers of oxidative stress in subjects with CVD risk factors.12,13,33,34
In this community-based cross-sectional study, we have confirmed this association, because we observed lower levels of glutathione and a more oxidized Eh
glutathione in the presence of risk factors and with metabolic syndrome. More importantly, we have also demonstrated that African Americans have higher oxidative stress, even after adjusting for racial differences in individual risk factor burden.
Recent animal studies have confirmed a link between intracellular levels of aminothiol markers of oxidative stress and progression of atherosclerosis. In apolipoprotein E–deficient (apo e−
) mice exposed to metabolic stress, a significant inverse correlation was found between macrophage glutathione content and cell-mediated oxidation of LDL. In addition, supplementation with a specific inhibitor of glutathione synthesis resulted in a 59% increase in atherosclerotic lesion size.35
Although these authors examined intracellular glutathione content and not plasma levels of glutathione, previous data indicate that release of glutathione from the intracellular to the extracellular space occurs as a function of intracellular tissue concentrations.36
These authors identified a novel aminothiol-dependent mechanism associated with the development of atherosclerotic lesions and may be related to previous data from our group associating markers of oxidative stress with carotid intima media thickness.33
Although our study has uniquely examined the relationship between race and aminothiol markers of oxidative stress, there are some limitations to our analysis. First, our data are cross-sectional and thus causality between racial differences in oxidative stress and disparities in CVD outcomes cannot be addressed specifically. Second, we did not measure other markers of oxidative stress such as isoprostanes or lipid hydroperoxides. However, racial differences in these markers of oxidative stress have been previously reported.26,28
Furthermore, because biologic systems generate more nonradical oxidants than free radicals, it is imperative to consider redox systems biology, because the amionothiols are a critical component of oxidative stress that is distinct from free radical–mediated macromolecular damage. Finally, levels of glutathione may be affected by vegetable intake in the diet; however, we did not incorporate this information into our analysis.29
In conclusion, African Americans had higher levels of aminothiol markers of systemic oxidative stress that were independent of traditional risk factor burden and inflammation. Furthermore, this racial disparity in oxidative burden was observed even in subjects who did not meet criteria for conventional risk assessment tools, like metabolic syndrome. The implications of our findings are that increased oxidative stress may contribute to observed racial disparities in CVD, because it is clear that traditional risk factors do not fully account for the observed differences. Estimation of oxidative stress with aminothiol markers may contribute to risk assessment, particularly in African Americans in whom traditional risk scores appear to underestimate their risk for future CVD events. Further studies are needed to confirm our findings in similar populations.