TY - JOUR
T1 - AT1-AA (angiotensin II type 1 receptor agonistic autoantibody) blockade prevents preeclamptic symptoms in placental ischemic rats
AU - Cunningham, Mark W.
AU - Castillo, Javier
AU - Ibrahim, Tarek
AU - Cornelius, Denise C.
AU - Campbell, Nathan
AU - Amaral, Lorena
AU - Vaka, Venkata Ramana
AU - Usry, Nathan
AU - Williams, Jan M.
AU - LaMarca, Babbette
N1 - Funding Information:
LaMarca. Funding supported by P20GM104357 and DK109133-01 awarded to J.M. Williams. D.C. Cornelius is supported by NIH grant HL130456 and the American Heart Association 16SDG27520000.
Funding Information:
This study was supported by National Institutes of Health (NIH) grants HL78147 and HL51971, and HD067541 awarded to B.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Women with preeclampsia produce AT1-AA (agonistic autoantibodies to the angiotensin II type 1 receptor), which stimulate reactive oxygen species, inflammatory factors, and hypertensive mechanisms (ET [endothelin] and sFlt-1 [soluble fms-like tyrosine kinase-1]) in rodent models of preeclampsia. The placental ischemic reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits many of these features. In this study, we examined the maternal outcomes of AT1-AA inhibition (n7AAc′) in RUPP rats. Blood pressure was higher in RUPP rats versus normal pregnant (NP) rats (123±2 versus 99±2 mm Hg, P<0.05), which was reduced in RUPP+n7AAc′ (105±3 versus 123±2 mm Hg, P<0.05 versus RUPP). Uterine artery resistant index was increased in RUPP versus NP rats (0.71±0.02 versus 0.49±0.02, P<0.05) and normalized in RUPP+n7AAc′ rats (0.55±0.03). Antiangiogenic factor sFlt-1 was elevated in RUPP versus NP rats (176±37 versus 77±15 pg/mL, P<0.05) but normalized in RUPP+n7AAc′ (86±9, P=0.05 versus RUPP). Plasma nitrate and nitrite were decreased (14±1 versus 20±1 μMNO3, P<0.05) and isoprostanes were elevated (20 117±6304 versus 2809±1375 pg/mL, P<0.05) in RUPP versus NP rats; and normalized in RUPP+n7AAc′ rats; (18±2 μMNO3; 4311±1 pg/mL). PPET-1 (preproendothelin-1) expression increased 4-fold in RUPP versus NP rats which were prevented with n7AAc′. Importantly, placental cytolytic natural killer cells were elevated in RUPP versus NP rats (8±2% versus 2±2% gated, P<0.05), which was prevented in RUPP+n7AAc′ total (3±1% gated, P<0.05) In conclusion, AT1-AA inhibition prevents the rise in maternal blood pressure and several pathophysiological factors associated with preeclampsia in RUPP rats and could be a potential therapy for preeclampsia.
AB - Women with preeclampsia produce AT1-AA (agonistic autoantibodies to the angiotensin II type 1 receptor), which stimulate reactive oxygen species, inflammatory factors, and hypertensive mechanisms (ET [endothelin] and sFlt-1 [soluble fms-like tyrosine kinase-1]) in rodent models of preeclampsia. The placental ischemic reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits many of these features. In this study, we examined the maternal outcomes of AT1-AA inhibition (n7AAc′) in RUPP rats. Blood pressure was higher in RUPP rats versus normal pregnant (NP) rats (123±2 versus 99±2 mm Hg, P<0.05), which was reduced in RUPP+n7AAc′ (105±3 versus 123±2 mm Hg, P<0.05 versus RUPP). Uterine artery resistant index was increased in RUPP versus NP rats (0.71±0.02 versus 0.49±0.02, P<0.05) and normalized in RUPP+n7AAc′ rats (0.55±0.03). Antiangiogenic factor sFlt-1 was elevated in RUPP versus NP rats (176±37 versus 77±15 pg/mL, P<0.05) but normalized in RUPP+n7AAc′ (86±9, P=0.05 versus RUPP). Plasma nitrate and nitrite were decreased (14±1 versus 20±1 μMNO3, P<0.05) and isoprostanes were elevated (20 117±6304 versus 2809±1375 pg/mL, P<0.05) in RUPP versus NP rats; and normalized in RUPP+n7AAc′ rats; (18±2 μMNO3; 4311±1 pg/mL). PPET-1 (preproendothelin-1) expression increased 4-fold in RUPP versus NP rats which were prevented with n7AAc′. Importantly, placental cytolytic natural killer cells were elevated in RUPP versus NP rats (8±2% versus 2±2% gated, P<0.05), which was prevented in RUPP+n7AAc′ total (3±1% gated, P<0.05) In conclusion, AT1-AA inhibition prevents the rise in maternal blood pressure and several pathophysiological factors associated with preeclampsia in RUPP rats and could be a potential therapy for preeclampsia.
KW - autoantibodies
KW - blood pressure
KW - isoprostanes
KW - pregnancy
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85054127877&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.117.10681
DO - 10.1161/HYPERTENSIONAHA.117.10681
M3 - Article
C2 - 29555668
AN - SCOPUS:85054127877
SN - 0194-911X
VL - 71
SP - 886
EP - 893
JO - Hypertension
JF - Hypertension
IS - 5
ER -