TY - JOUR
T1 - Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia
AU - Vaka, Venkata Ramana
AU - Cunningham, Mark W.
AU - Deer, Evangeline
AU - Franks, Michael
AU - Ibrahim, Tarek
AU - Amaral, Lorena M.
AU - Usry, Nathan
AU - Cornelius, Denise C.
AU - Dechend, Ralf
AU - Wallukat, Gerd
AU - LaMarca, Babbette D.
N1 - Funding Information:
This research was supported by National Institutes of Health Grants RO1-HD-067541 and P20-GM-121334 (B. D. LaMarca) and R00-HL-103456 (D. C. Cornelius) and American Heart Association predoctoral fellowship 17PRE33660592/ AHA (V. R. Vaka).
Publisher Copyright:
© 2020 American Physiological Society. All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide (=n7AAc=). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + =n7AAc=). On day 14 of gestation (GD), RUPP surgery was performed; =n7AAc= peptide (2 μg/μL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + =n7AAc= rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + =n7AAc= sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.
AB - Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide (=n7AAc=). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + =n7AAc=). On day 14 of gestation (GD), RUPP surgery was performed; =n7AAc= peptide (2 μg/μL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + =n7AAc= rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + =n7AAc= sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.
KW - AT-AAs and preeclampsia
KW - Mitochondrial dysfunction
KW - Mitochondrial reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85078512298&partnerID=8YFLogxK
U2 - 10.1152/AJPREGU.00179.2019
DO - 10.1152/AJPREGU.00179.2019
M3 - Article
C2 - 31721604
AN - SCOPUS:85078512298
SN - 0363-6119
VL - 318
SP - R256-R262
JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
IS - 2
ER -