Abstract
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.
Highlights
Hypertension is a major cause of death and disability worldwide
The mRNA expression data was imported into Ingenuity Pathway Analysis (IPA) to match against curated hypertension-related gene sets and 118 mRNAs were significantly- and differentially-expressed between groups in our cohort (Fig. 2F, Supplementary Excel File 1). 46 mRNAs were elevated in AAHT compared with AANT, and 13 mRNAs were significantly down (Fig. 2G)
We observed that several mRNAs were significantly increased in peripheral blood mononuclear cells (PBMCs) in AAHT compared with AANT, including Myeloid cell leukemia sequence 1 (MCL1), apolipoprotein L3 (APOL3), phospholipase D1 (PLD1), RHOA, and PTK2B (Fig. 6)
Summary
Hypertension is a major cause of death and disability worldwide. In the United States, almost 30% of the US population over age 18 have hypertension; African Americans (AA) have the highest prevalence of hypertension and cardiovascular disease (CVD) in the United States and have higher mortality attributed to CVDs than whites[1]. In peripheral blood mononuclear cells (PBMCs), healthy AA men have higher mRNA levels of angiotensin II type I receptor (AGTR1) than healthy white men and exhibit increased production of superoxide, potentially contributing to oxidative stress and inflammatory states in healthy AA men[6] These studies are among the few that examine gene expression differences which may play a role in racial hypertension disparities, but they are limited as they do not investigate the regulatory mechanisms governing these observed differences. One study identified five differentially-expressed miRNAs in PBMCs from hypertensives which correlated with blood pressure, including miRs-143, -145, -133, -21- and -117 These miRNAs were examined because they regulate vascular smooth muscle cell differentiation and function, how these miRNAs contribute to hypertension etiology requires further evaluation. These include hypertension-related mRNAs previously identified in GWAS analysis, such as SH2B3 and PLEKHA719
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