Systemic arterial hypertension is an important cause of cardiovascular disease morbidity and mortality. African Americans are disproportionately affected by hypertension, in fact the incidence, prevalence, and severity of hypertension is highest among African American (AA) women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases and we hypothesized that this phenomena may affect health disparities in hypertension. Transcriptional profiling of peripheral blood mononuclear cells from AA or white, normotensive or hypertensive females identified thousands of mRNAs differentially-expressed by race and/or hypertension. Predominant gene expression differences were observed in AA hypertensive females compared to AA normotensives or white hypertensives. Since microRNAs play important roles in regulating gene expression, we profiled global microRNA expression and observed differentially-expressed microRNAs by race and/or hypertension. We identified novel mRNA-microRNA pairs potentially involved in hypertension-related pathways and differently-expressed, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR-4717-3p, and PLD1/miR-4709-3p. We validated gene expression levels via RT-qPCR and microRNA target validation was performed in primary endothelial cells. Altogether, we identified significant gene expression differences between AA and white female hypertensives and pinpointed novel mRNA-microRNA pairs differentially-expressed by hypertension and race. These differences may contribute to the known disparities in hypertension and may be potential targets for intervention.

C-reactive protein (CRP), an acute-phase plasma protein, is a major component of inflammatory reactions functioning as a mediator of innate immunity. It has been widely used as a validated clinical biomarker of the inflammatory state in trauma, infection, and age-associated chronic diseases, including cancer and cardiovascular disease (CVD). Despite this, the molecular mechanisms that regulate CRP expression are not well understood. Given that the CRP 3= untranslated region (UTR) is long and AU rich, we hypothesized that CRP may be regulated posttranscriptionally by RNA-binding proteins (RBPs) and by microRNAs. Here, we found that the RBP HuR bound directly to the CRP 3= UTR and affected CRP mRNA levels. Through this interaction, HuR selectively increased CRP mRNA stability and promoted CRP translation. Interestingly, treatment with the age-associated inflammatory cytokine interleukin-6 (IL-6) increased binding of HuR to CRP mRNA, and conversely, HuR was required for IL-6-mediated upregulation of CRP expression. In addition, we identified microRNA 637 (miR-637) as a microRNA that potently inhibited CRP expression in competition with HuR. Taken together, we have uncovered an important posttranscriptional mechanism that modulates the expression of the inflammatory marker CRP, which may be utilized in the development of treatments for inflammatory processes that cause CVD and age-related diseases.I nflammatory processes and their inherent regulatory controls are critical for the immune response to injury and pathogens throughout the life span. However, inflammation has now been identified as an important underlying factor in many chronic diseases, including cardiovascular disease (CVD), diabetes mellitus, cancer, and metabolic disorders. Age itself is a critical factor in the development of the inflammatory state and risk for these conditions. This age-associated inflammatory state, known as inflammaging, is defined as a state of low-grade, sterile inflammation that occurs with age and is characterized by elevations of serum concentrations of proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-␣), as well as the acute-phase reactant C-reactive protein (CRP) (1). Given the incidence, morbidity, and mortality of inflammation-based chronic disease, proinflammatory molecules, including CRP, are avidly studied.CRP, a pentraxin protein, is an established marker of acutephase reactions (2). It is an important inflammatory biomarker that is influenced by the action of numerous activated cytokines, such as IL-6, IL-1␤, and TNF-␣ (3, 4). It is well established that circulating levels of CRP and IL-6 are correlated in humans (5, 6). CRP has been widely used as a validated clinical biomarker of the inflammatory state and an independent predictor of cardiovascular disease. There is some evidence that CRP is not only a biomarker of cardiovascular and metabolic disease but also a specific risk factor for disease, with some data supporting the idea that CRP is an active participant in ath...

Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension. To explore this mechanism, we identified two miRNAs, miR-103a-2-5p and miR-585-5p, that are differentially expressed with hypertension and were predicted to target PARP1. Through overexpression of each miRNA-downregulated PARP-1 mRNA and protein levels and using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP1 through binding within the coding region. Given the important 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. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new miRNA regulators of PARP-1 expression. These insights may provide additional avenues to understand hypertension health disparities.

Growth differentiation factor 15 (GDF15) is a multifunctional, secreted protein that is a direct target gene of p53. GDF15 is a prospective biomarker of cardiovascular disease (CVD). C-reactive protein (CRP), like GDF15, is implicated in inflammation and an independent biomarker of CVD. However, the molecular interactions between GDF15 and CRP remain unexplored. In women, we found a significant relationship between hsCRP and GDF15 serum and mRNA levels. In vitro treatment of cultured human aortic endothelial cells (HAECs) with purified CRP or transfection of a CRP plasmid into HAECs induced GDF15 expression. Dual-luciferase reporter assays confirmed that CRP significantly increased the levels of GDF15 promoter luciferase activity, indicating that CRP induces GDF15 transcription. Chromatin immunoprecipitation (ChIP) assays confirmed that p53 was recruited to both p53 binding sites 1 and 2 in the GDF15 promoter in response to CRP. We have uncovered a linkage between CRP and GDF15, a new clue that could be important in the pathogenesis of endothelial inflammation.

Mortality disparities are influenced by race and poverty. There is limited information about whether poverty influences biologic markers of mortality risk. Emerging data suggests that growth differentiation factor 15 (GDF15) is associated with mortality; however, the interplay between GDF15, sociodemographic factors and mortality is not known. We sought to evaluate the interactions between GDF15 and sex, race and poverty status on mortality. Serum GDF15 was measured in 1036 African American and white middle-aged men and women above and below 125% of the Federal poverty status from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Multivariable adjusted Cox regression models were used to assess the association between log-transformed GDF15 (logGDF15) and 12-year mortality outcomes (all-cause, cardiovascular-and cancer-specific outcomes) and interactions with sex, race and poverty status. Likelihood ratio tests were used to assess significance of the interaction terms. Median GDF15 was 655.2 pg/mL (IQR = 575.1). During 12.2 years of follow-up, 331 died of which 94 cardiovascular-and 87 were cancer-specific deaths. One unit of increase in logGDF15 was associated with a hazard ratio for all-cause mortality, cardiovascular-and cancer-specific mortality of 2.26 (95% confidence interval [CI], 1.94-2.64), 2.74 (95%CI, 2.06-3.63) and 1.41 (95%CI, 1.00-2.00), respectively. There was an interaction between logGDF15 and poverty status on all-cause mortality (p<0.05). The GDF15×poverty status interaction term improved model calibration for all-cause mortality. Our study provides the first evidence that the effect of elevated GDF15 on all-cause mortality is modified by poverty status. Background Although overall mortality rates continue to decline in the United States, recent trends document disproportionate increases in mortality and life expectancy amongst groups in the United States [1]. Notably, age-adjusted death rates for non-Hispanic African American men

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