Abstract
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.
Highlights
Systemic arterial hypertension, an age-associated chronic disease, is a predictor of vascular-associated mortality from stroke and ischemic heart disease [1, 2]
We observed that gene expression in Oxidative Medicine and Cellular Longevity hypertension-related pathways, in renin-angiotensin-aldosterone system (RAAS) and other inflammatory pathways, was significantly upregulated in AA hypertensives compared with both normotensive controls and white hypertensives [7]
We previously reported that there is significant, differential mRNA and miRNA expression by race and/or hypertension status in peripheral blood mononuclear cells (PBMCs) isolated from AA and white women
Summary
An age-associated chronic disease, is a predictor of vascular-associated mortality from stroke and ischemic heart disease [1, 2]. It affects more than 80 million people ≥ 20 years old in the United States with increased prevalence over the lifespan [2]. Perturbations in the renin-angiotensin-aldosterone system (RAAS) and nitric oxide (NO) pathway in immune cells and in the endothelium can contribute to the development of hypertension [4, 5], but how these pathways influence disparities in hypertension etiology is not clear. We observed that gene expression in Oxidative Medicine and Cellular Longevity hypertension-related pathways, in RAAS and other inflammatory pathways, was significantly upregulated in AA hypertensives compared with both normotensive controls and white hypertensives [7]
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