Our initial work focused on understanding DNA repair parameters on a population basis in the Healthy Aging in Neighborhood across the Life Span (HANDLS). However, our work on DNA repair and particularly oxidative DNA damage and oxidative stress that showed a positive correlation between SSBs in African American males with both two markers of oxidative stress and inflammation, heme-degradation products and high-sensitivity C-reactive protein (hs-CRP) led us to further pursue the complex relationship between measures of oxidative stress and frequently used clinical parameters believed to reflect inflammation or oxidative stress. Hence this year our work has focused largely on CRP. Since hs-CRP is linked to chronic inflammation that is a consequence of oxidative stress, it is relevant to examine the importance of hs-CRP as a biomarker of disease states related to oxidative stress. Accumulating evidence indicates that the levels of hsCRP are important for assessment of cardiovascular disease (CVD) risk and for the diagnosis and treatment of CVD. Recent data suggests that hsCRP is not only a marker of inflammation but may also contribute to the pathogenesis of vascular disease. However, whether hsCRP plays a direct role in promoting atherosclerotic processes is still controversial and little is known about how hsCRP may elicit these effects. Nonetheless, important information has been obtained from correlating findings discovered from human populations to in vitro studies. Since our work has shown that women had higher levels of DNA damage and lower levels of DNA repair, and it is known that women have higher levels of hsCRP than men and are particularly vulnerable to CVD we were anxious to examine the association between inflammation and oxidative stress by examining commonly assayed inflammatory markers and the DNA base adduct 8-oxodG, as a marker of oxidative stress in a cohort of middle-aged women with low, mid-range, and high hsCRP values. In the HANDLS cohort of women, matched on age and race in three groups (n=39 per group) who had low (<3 mg/L) hsCRP, mid (>320 mg/L), and high (>20 mg/L) hsCRP, we found a significant relationship between hsCRP level and the oxidative stress marker, 8-oxodG. 8-oxodG was positively correlated with systolic blood pressure, pulse pressure and IL-23. hsCRP was associated with obesity variables, HDL, serum insulin levels, IL-12p70 and ICAM-1. Incubation of primary human endothelial cells with hsCRP generated reactive oxygen species in vitro. Furthermore, hsCRP specifically induced DNA base lesions, but not other forms of DNA damage including single and double strand breaks. Our findings suggest that hsCRP production may enhance inflammatory processes, such as atherosclerosis and thrombosis, in part, by increasing oxidative stress and inducing DNA damage. As CRP is a stress response protein, we hypothesize that post-transcriptional regulatory factors bind and regulate CRP mRNA and are actively examining the possible post-transcriptional regulation of CRP. In addition, since hsCRP is predictive for cardiovascular events, it has become increasingly important to understand the relationship of hsCRP to other inflammatory and oxidative stress markers as a segue to assess the molecular pathways that link inflammation and oxidative stress in cardiovascular disease (CVD) etiology. Recent data indicates that brain-derived neurotrophic factor (BDNF) may have a role in CVD. Therefore, we examined BDNF levels in 3 groups of women that were age and race-matched with low (<3 mg/L), mid (>320 mg/L), and high (>20 mg/L) hsCRP (n=39 per group) and found a significant association between hsCRP, BDNF and 8-oxodG. In African American females with high hsCRP, increases in BDNF were associated with decreased serum 8-oxodG. This was not the case in white women where high hsCRP were associated with high levels of BDNF and high levels of 8-oxodG. BDNF treatment of cells reduced CRP levels and inhibited CRP-induced DNA damage. Through this work, we discovered an important relationship between hsCRP, 8-oxodG and BDNF in women at hsCRP levels >3 mg/L. These data suggest that BDNF may have a protective role in counteracting the inflammatory effects of hsCRP. Important in the study of chronic disease and inflammation is the discovery of new biomarkers that serve as indicators of tissue age and development and that also can aid in the diagnosis of age-related diseases. Among these are microRNAs (miRNAs). miRNAs are key regulators of gene expression and a variety of cellular processes. However, little is known about how these small RNAs contribute to human aging and chronic disease. We have surveyed expression of miRNAs from young and old HANDLS participants in order to provide a genome-wide assessment of miRNA expression during human aging. Interestingly, we found that most miRNAs are downregulated in older participants compared to younger participants, which is consistent with microarray data from both C. elegans and senescent cells in vitro. Future studies will examine the differential expression of miRNAs in systemic arterial hypertension examining differential expression between African Americans and whites as well as between hypertensive and normotensive participants. Preliminary data in our lab suggests that there are significant expression differences between hypertensive and non-hypertensive individuals as well as among African Americans and whites. Circulating serum miRNAs are now considered a novel class of potentially useful non-invasive biomarkers in the detection of early disease, monitoring disease progression and stratifying disease risk. Work in the laboratory has also begun on understanding the role of Dicer, an important processor of microRNAs (miRNAs) in cells that may also be important in the regulation of a variety of biological processes including aging and chronic disease susceptibility. Other ongoing work in the laboratory focuses examining other potential biomarkers of aging and chronic disease that are relevant to health disparities including extracellular vesicles as well as genetic phenotypes associated with increased cardiovascular risk.
NIH ExPorter
NIH ExPorter