Angiotensin II type 1 receptor agonistic autoantibody blockade improves postpartum hypertension and cardiac mitochondrial function in rat model of preeclampsia

Abstract

Women with preeclampsia (PE) have a greater risk of developing hypertension, cardiovascular disease (CVD), and renal disease later in life. Angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE during pregnancy and up to 2-year postpartum (PP), and in the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of AT1-AA with a specific 7 amino acid peptide binding sequence (‘n7AAc’) improves pathophysiology observed in RUPP rats; however, the long-term effects of AT1-AA inhibition in PP is unknown. Pregnant Sprague Dawley rats were divided into three groups: normal pregnant (NP) (n = 16), RUPP (n = 15), and RUPP + ‘n7AAc’ (n = 16). Gestational day 14, RUPP surgery was performed and ‘n7AAc’ (144 μg/day) administered via osmotic minipump. At 10-week PP, mean arterial pressure (MAP), renal glomerular filtration rate (GFR) and cardiac functions, and cardiac mitochondria function were assessed. MAP was elevated PP in RUPP vs. NP (126 ± 4 vs. 116 ± 3 mmHg, p < 0.05), but was normalized in in RUPP + ‘n7AAc’ (109 ± 3 mmHg) vs. RUPP (p < 0.05). PP heart size was reduced by RUPP + ’n7AAc’ vs. RUPP rats (p < 0.05). Complex IV protein abundance and enzymatic activity, along with glutamate/malate-driven respiration (complexes I, III, and IV), were reduced in the heart of RUPP vs. NP rats which was prevented with ‘n7AAc’. AT1-AA inhibition during pregnancy not only improves blood pressure and pathophysiology of PE in rats during pregnancy, but also long-term changes in blood pressure, cardiac hypertrophy, and cardiac mitochondrial function PP.

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

“…In RUPP rodents, the number and size of uterine spiral arterioles decreases and the expression of MMP-2 and MMP-9 in uterus and uterine arteries is lower. Several therapeutic candidates, including 17-alpha-hydroxyprogesterone, pravastatin, sildenafil, interleukin (IL)-10, vitamin D, placental growth factor, relaxin, liraglutide, sonic hedgehog protein, low dose IL-2, IL-25, an angiotensin II type 1 receptor autoantibody blockade peptide, Etanercept, a hydrogen sulfide releasing molecule MZe786, l -(+)-ergothioneine, a soluble IL-17 receptor IL-17RC, and apelin, as well as interferon γ neutralization, have been found to reduce hypertension in RUPP animals to varying degrees [78–96]. However, only a few candidates, such as IL-25, Etanercept, IL-17RC, and MZe786, have been found to significantly mitigate FGR in RUPP animals [92–95].…”

“…The RUPP model is characterized by placental ischemia, maternal endothelial dysfunction, and increased vascular resistance and stiffness [75][76][77]. It was used to evaluate the translational potential of various therapeutic candidates on pregnancy-associated hypertension and fetal growth restriction [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96]. Although this rodent model is not ideal for modeling preeclampsia in humans, this proof-of-concept study demonstrated that ADE101 could be a promising candidate for improving vascular homeostasis in patients with pregnancy-associated hypertension and fetal growth restriction.…”

Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association

“…49 In addition, AT 1 R autoantibody blockade during pregnancy in the reduced uterine perfusion pressure model improves maternal blood pressure during pregnancy and maternal blood pressure, cardiac hypertrophy, and cardiac mitochondrial function 10 weeks postpartum. 50 However, much more investigation is needed to better delineate the role of the RAAS in mediating maternal antenatal hypertension programming.…”

Is Mitochondrial Oxidative Stress a Viable Therapeutic Target in Preeclampsia?

“…These exciting findings prompted research groups to explore mitochondrial bioenergetics in organ systems beyond placenta or kidneys. For instance, a recent study published by Booz et al demonstrated that isolated cardiac mitochondria from RUPP rats show reduced mitochondrial respiration and Complex IV activity [ 45 ]. Further, Sánchez-Aranguren et al reported that overexpression of sFlt1 in heme oxygenase-1-deficient mice causes mitochondrial dysfunction in cardiac mitochondria [ 46 ].…”