Abstract 145: Central Angiotensin-(1-7) Treatment Attenuates ERK 1/2 Expression and Oxidative Stress in the Dorsal Medulla of Betamethasone-Exposed Sheep That Associates With Improved Blood Pressure and Baroreflex Sensitivity

Abstract

Fetal exposure to betamethasone (BMX) that is routinely administered to women threatening premature delivery may lead to deleterious long-term effects on the central cardiovascular system. In the adult offspring of BMX-exposed sheep, we demonstrate increased mean arterial pressure (MAP) and attenuated baroreflex sensitivity (BRS). These responses are associated with dysregulation of the brain renin-angiotensin system (RAS) reflecting lower medullary expression of Angiotensin-(1-7) [Ang-(1-7)] and its beneficial actions. Moreover, mitogen activated protein kinase (MAPK), a key signaling cascade implicated in cardiovascular dysfunction and stimulation of oxidative stress is increased in the brain dorsomedial medulla (DMM). We hypothesize that loss of Ang-(1-7) tone with BMX is an underlying mechanism for the programming effects to increase MAPK and oxidative stress. Thus, we examined whether intracerebroventricular treatment with Ang-(1-7) that lowers MAP and improves BRS will impact MAPK signaling and downstream generation of reactive oxygen species (ROS). MAPK activation as detected by the ratio of phospho-ERK 1/2 to total ERK densities was significantly reduced by >80% in the Ang-(1-7)-treated BMX sheep as compared to the CSF-treated BMX controls (0.20 ± 0.07 vs 1.04 ± 0.31; p = 0.01, N=4/group). Ang-(1-7) treatment was associated with lower expression of two indices of ROS including 4-HNE (0.23 ± 0.03 vs. 0.31 ± 0.03 p = 0.03) and protein carbonyl content (9.95 ± 0.69 vs 15.94 ± 3.49; p = 0.07). Finally, regression analysis revealed that phospho-ERK 1/2 expression positively correlated with ROS (4-HNE) (r = 0.816; p = 0.01). The 4-HNE content also trended positively with MAP (r = 0.659, p = 0.08), but exhibited a negative correlation with BRS (r = -0.831; p = 0.01). We conclude that reduced central Ang-(1-7) tone may contribute to the chronic dysregulation of the MAPK and ROS signaling pathways within the DMM following BMX exposure. Moreover, Ang-(1-7) may constitute a potential therapeutic approach to improve autonomic dysfunction by attenuating both MAPK and ROS pathways. HD 047584.