Selective Nrf2 Gene Deletion in the Rostral Ventrolateral Medulla Evokes Hypertension and Sympathoexcitation in MiceNovelty and Significance
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Nuclear factor erythroid 2–related factor 2 (Nrf2) is a master transcriptional regulator of redox homeostasis that impacts antioxidant gene expression. Central oxidative stress and reduced antioxidant enzyme expression in the rostral ventrolateral medulla (RVLM) contributed to sympathoexcitation in chronic heart failure. In the current study, we hypothesized that deletion of Nrf2 in the RVLM would increase sympathetic drive and blood pressure. Experiments were performed in Nrf2-floxed mice treated with microinjection of lentiviral-Cre-GFP or lentiviral-GFP into the RVLM. Two weeks after viral administration, Nrf2 message, protein, oxidative stress, cardiovascular function, and sympathetic outflow were evaluated. We found that (1) Nrf2 mRNA and protein in the RVLM were significantly lower in Cre mice compared with control GFP mice. Nrf2-targeted antioxidant enzymes were downregulated, whereas reactive oxygen species were elevated. (2) Blood pressure measurements indicated that Cre mice displayed a significant increase in blood pressure (mean arterial pressure, 123.7±3.8 versus 100.2±2.2 mm Hg; P<0.05, n=6), elevated urinary norepinephrine (NE) concentration (456.4±16.9 versus 356.5±19.9 ng/mL; P<0.05, n=6), and decreased spontaneous baroreflex gain (up sequences, 1.66±0.17 versus 3.61±0.22 ms/mm Hg; P<0.05, n=6; down sequences, 1.89±0.12 versus 2.98±0.19 ms/mm Hg; P<0.05, n=6). (3) Cre mice displayed elevated baseline renal sympathetic nerve activity and impaired inducible baroreflex function. These data suggest that Nrf2 gene deletion in the RVLM elevates blood pressure, increases sympathetic outflow, and impairs baroreflex function potentially by impaired antioxidant enzyme expression.
- Received January 22, 2017.
- Revision received February 5, 2017.
- Accepted March 6, 2017.
- © 2017 American Heart Association, Inc.