We have continued our work examining the biology of health disparities because it is through biological mechanisms that social determinates of health result in disparate health outcomes. Notable results from this year include studies on differential gene expression by race in systemic arterial hypertension in women and the effect of perceived discrimination on renal function. African Americans (AAs) are disproportionately affected by hypertension and the incidence, prevalence, and severity of hypertension is highest among AA women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases. We hypothesized that this may affect health disparities in hypertension. We profiled mRNA expression levels in peripheral blood mononuclear cells (PBMCs) isolated from AA or white, normotensive or hypertensive females and identified thousands of mRNAs significantly and differentially-expressed by race and hypertension status. Profound gene expression differences were observed in AA hypertensive females compared with all other groups. AA hypertensive females have significantly elevated expression of inflammatory genes and pathways when compared to AA normotensive controls or white hypertensives. We next sought to understand the mechanism that contributes to differential gene expression patterns in AA hypertensive females. Considering microRNAs play important roles in modulating mRNA expression levels, we profiled global microRNA expression and observed 36 microRNAs that were significantly and differentially-expressed by race and hypertension status. We performed bioinformatic microRNA target prediction analyses to identify novel mRNA-microRNA pairs involved with inflammation-related pathways and which were also differentially-expressed by race. We identified several novel pairs, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR-4717-3p, and PLD1/miR-4709-3p, never associated with hypertension and we validated our predicted mRNA-microRNA interactions in primary endothelial cells. Altogether, we identified significant gene expression differences between AA and white hypertensive females and pinpointed novel mRNA-microRNA pairs differentially-expressed by hypertension and race. These novel findings enhance our understanding of hypertension in AA females and provide potential new avenues for therapeutic intervention. Since we identified miRNAs differentially expressed by race and/or hypertension in African American and white women, we focused on two of the miRNAs identified to better understand mechanistically how they may contribute to hypertension. Using bioinformatic analysis based on our gene and miRNA expression levels in hypertensives and subsequent target validation, we found that miR-103a-2-5p and miR-585-5p both target the DNA damage sensor and repair protein Poly-(ADP-ribose) polymerase 1 (PARP-1). Overexpression of these two miRNAs downregulated PARP-1 mRNA and protein levels in primary endothelial cells. Using heterologous luciferase reporter assays, we demonstrated that miR-103a-2-5p and miR-585-5p regulate PARP-1 through binding to sites in the coding region. Given the role of PARP-1 in DNA repair, we assessed whether overexpression of miR-103a-2-5p or miR-585-5p affected DNA damage and cell survival. Overexpression of these miRNAs enhanced DNA damage and decreased both cell survival and colony formation. In the context of racial differences in hypertension, we observed higher levels of PARP-1 in African American Hypertensives (AAHT) compared to African American Normotensives. PARP-1 levels were also higher in AAHT compared to White Hypertensives (WHT), but not WHT compared to White Normotensives. AA women with hypertension exhibit elevated expression of genes in oxidative stress and DNA damage response pathways. These data suggest that differential PARP-1 expression is important in hypertension and may have a racial component. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new regulators of PARP-1 expression, miR-103a-2-5p and miR-585-5p. Our data identifies genomic factors that appear to differentially influence the presence of hypertension among African American and white women. These findings may be useful in developing personalized medicine approaches to the treatment of hypertension in populations at disproportionate risk.
| Kim, Yoonseo; Noren Hooten, Nicole; Evans, Michele K (2018) CRP Stimulates GDF15 Expression in Endothelial Cells through p53. Mediators Inflamm 2018:8278039 |
| DeMarino, Catherine; Pleet, Michelle L; Cowen, Maria et al. (2018) Antiretroviral Drugs Alter the Content of Extracellular Vesicles from HIV-1-Infected Cells. Sci Rep 8:7653 |
| Eitan, Erez; Green, Jamal; Bodogai, Monica et al. (2017) Age-Related Changes in Plasma Extracellular Vesicle Characteristics and Internalization by Leukocytes. Sci Rep 7:1342 |
| Noren Hooten, Nicole; Evans, Michele K (2017) Techniques to Induce and Quantify Cellular Senescence. J Vis Exp : |
| Dluzen, Douglas F; Noren Hooten, Nicole; Evans, Michele K (2017) Extracellular RNA in aging. Wiley Interdiscip Rev RNA 8: |
| Dluzen, Douglas F; Kim, Yoonseo; Bastian, Paul et al. (2017) MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation. Oxid Med Cell Longev 2017:3984280 |
| Plank-Bazinet, Jennifer L; Kornstein, Susan G; Clayton, Janine Austin et al. (2016) A Report of the Women's Health Congress Workshop on The Health of Women of Color: A Critical Intersection at the Corner of Sex/Gender and Race/Ethnicity. J Womens Health (Larchmt) 25:4-10 |
| Chami, Nathalie; Chen, Ming-Huei; Slater, Andrew J et al. (2016) Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. Am J Hum Genet 99:8-21 |
| Dluzen, Douglas F; Noren Hooten, Nicole; Zhang, Yongqing et al. (2016) Racial differences in microRNA and gene expression in hypertensive women. Sci Rep 6:35815 |
| Noren Hooten, Nicole; Martin-Montalvo, Alejandro; Dluzen, Douglas F et al. (2016) Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15:572-81 |
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