Inhibition of Angiotensin II Type I Receptor Agonistic Autoantibody Reduces Mitochondrial Mediated Oxidative Stress and Hypertension in Reduced Uterine Perfusion Pressure Rats
Authors: Vaka V. Ramana , Cunningham Mark W , Shirey Kristin , Ibrahim Tarek , Hosler Jonathan , LaMarca Babbette 
Published: November 2023

Introduction

Preeclampsia is characterized by new onset hypertension that usually occurs in the 3rd trimester of pregnancy, and is associated with oxidative stress and increased plasma levels of angiotensin II type 1 receptor agonistic autoantibodies (AT1‐AA). Inhibition of the AT1‐AA in the reduced uterine perfusion pressure (RUPP) rats, a model of preeclampsia, decreases the blood pressure and oxidative stress. Although there is a decrease in overall oxidative stress, the changes in mitochondrial mediated oxidative stress has not been explored with AT1‐AA inhibition in the RUPP rat. We hypothesize that AT1‐AA inhibition prevents mitochondrial dysfunction and decreases mitochondrial mediated reactive oxygen species (ROS) in the RUPP rat.

Methods

Female Sprague Dawley rats were dived into three groups; normal pregnant (NP), RUPP, and RUPP + AT1‐AA inhibition (RUPP+7AA). AT1AA inhibition was achieved by administration of a 7 amino acid epitope binding peptide that inhibits the AT1‐AA from binding to the AT1 receptor. On day 14 of gestation, the RUPP surgery was performed with or without the 7AA peptide (2μg/ml saline) administered via mini‐osmotic pumps. On day 19 of gestation, conscious mean arterial blood pressure (MAP) was measured in RUPP and normal pregnant (NP) rats, placentas were collected for histology and isolation of mitochondria. Dihydroethidium (DHE, 10 μmol/L) staining was performed to determine placental superoxide levels. Isolated mitochondria from placentas were used to measure ROS and enzyme activities of Complex I and IV of the electron transport chain. All rats were age matched to control.

Results

Mean arterial blood pressure was higher in RUPPs (n=8; 125± 6 mmHg) vs NPs (n=7; 98±3 mmHg). RUPPs treated with 7AA (n=8; 103± 6 mmHg) showed a significant reduction in blood pressure vs RUPP rats. Superoxide levels were elevated in the placenta of RUPP vs NP rats, and was lowered in RUPP+7AA treated rats. The enzyme activities of Complex I (160 nmol/e‐/min/mg) and Complex IV (501 nmol/e‐/min/mg) in RUPP rats were reduced compared to NPs (198 and 686 nmol/e‐/min/mg respectively). AT1‐AA inhibition improved Complex I and IV activities (198 and 756 nmol/e‐/min/mg respectively) vs RUPPs. ROS levels were higher in the placental mitochondria of RUPP vs NP (15× 10−3 vs 5× 10−3, relative units normalized to Complex IV activity). RUPPs that received 7AA peptide showed a decreased ROS levels (13× 10−3, relative units, normalized to complex IV activity).

Conclusion

Inhibition of AT1AA reduces the blood pressure, placental superoxide levels, mitochondrial electron transport chain activity, and mitochondrial ROS production in RUPP rats. Our data suggest that AT1‐AA inhibition could serve as a novel therapy to reduce mitochondrial mediated oxidative stress in preeclampsia.

Support or Funding Information

Research Supported by RO1HD067541