MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation

Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases. Here we report that the Poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated with hypertension in African American women. To further explore this mechanism, we identified two microRNAs, miR-103a-2-5p and miR-585-5p that are differentially-expressed with hypertension and were predicted to target PARP-1. Overexpression of these two miRNAs downregulated PARP-1 mRNA and protein levels in primary endothelial cells. Using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP-1 through binding to sites in 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 regulators of PARP-1 expression, miR-103a-2-5p and miR-585-5p. Additionally, these insights may provide additional avenues to understand hypertension health disparities Primary human endothelial aortic cells (HAECs) were transfected with either pre-miR miRNA precursors for hsa-miR-103a-2-5p, miR-585-5p, or scrambled negative control (Control), and the transcriptional changes examined by gene expression microarray analysis using three biological repeats of each experimental condition.