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.
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 years 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 3 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 weeks 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.
Preeclamptic (PE) women have placental ischemia, hypertension (HTN), mitochondrial (mt) dysfunction, increased mt-reactive oxygen species (ROS), cytolytic natural killer (NK) cells, and pro-inflammatory cytokines, such as tumor necrosis factor (TNFα). The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE, is a well-established model to study mechanisms of hypertension in response to placental ischemia during pregnancy. Previous studies from our lab have shown that TNFα is elevated in RUPP rats and that blockade of TNFα, via etanercept (ETAN) decreases TNFα and HTN. However, the effect of TNFα blockade on NK cell activation, mt protein/function, and mtROS is unknown. We hypothesized that ETAN would decrease blood pressure, NK cell activation, mtROS, and improve mt function in RUPP rats. Rats were divided into 4 groups: normal pregnant (NP) (n=41), RUPP (n=34), RUPP+low dose (LD) ETAN (0.4 mg/kg) (n=11), RUPP+high dose (HD) ETAN (0.8 mg/kg) (n=19). LD was used previously, while HD is clinically used to treat chronic inflammatory diseases. Gestational day 14, RUPP surgery was performed and ETAN administered subcutaneous on day 18. Day 19, conscious blood pressure (MAP), blood and tissues were collected, and mt were isolated. Flow cytometry was used for quantification of NK cells. MAP was elevated in RUPP vs. NP (119 ± 1 vs. 102± 1 mmHg, p<0.05) which was reduced to 110 ± 2 in RUPP + LD ETAN (p<0.05 vs. RUPP) and 116 ± 1 in RUPP + HD ETAN. Activated NK cells were increased in circulation (5.9 ± 1.8 vs. 4.0 ± 1.4 %), placenta (4.8 ± 1.3 vs. 1.9 ± 0.7 %), and kidneys (3.1 ± 0.5 vs. 0.8 ± 0.5%) of RUPP vs. NP (p<0.05). Both LD (2.1 ± 0.7%, 1.7 ± 0.7%, 0.8 ± 0.5%) and HD (0.2 ± 0.1%, 0.4 ± 0.1%, 0.8 ± 0.2%) ETAN decreased activated NK cells in circulation, placenta, and kidney respectively (p<0.05 vs RUPP). Placental (0.79± 0.02 vs 1±0.05 fold) and renal (0.67± 0.05 vs 1±0.06 fold) mtROS was reduced with LD ETAN vs RUPP (p<0.05). ETAN treatment lowers blood pressure and reduces circulating, placental, and renal activated NK cells and mtROS in placental ischemic rats. Therefore ETAN could be a potential therapeutic for improving HTN, inflammation, and mitochondrial function during complicated pregnancies. Supported: AHA18CDA34110264, HL130456, R01HD067541, & P20GM121334
Women with preeclampsia (PE) have a risk of developing cardiovascular diseases (CVD) later in life. The angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE, PE women 2 years post-partum (PP), and the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of the AT1-AA by using a specific binding seven amino acid peptide sequence (7AA) improves the pathology of PE in RUPP rats. The long-term effects of AT1-AA inhibition on blood pressure, NK cell activation, heart mitochondria (mt) proteins, and CVD in the RUPP model PP is unknown. Therefore, we hypothesized that PP RUPP rats have elevated blood pressure, NK cell activation, and changes in heart mt proteins, which will be prevented in RUPP rats administered the 7AA during pregnancy. Methods: Pregnant Sprague Dawley rats were divided into groups; normal pregnant (NP) (n=7), RUPP (n=10), and RUPP+7AA (n=9). Gestational day 14, RUPP surgery was performed and 7AA (2 μg/ml) administered via minipump. Results: At 8 and 10 weeks (wks) PP, blood pressure (MAP), blood, and hearts were collected. NK cells were quantified by flow cytometry. At 8 wks PP, MAP was elevated in RUPP vs. NP (130±2 vs. 123±4 mmHg, ns), and RUPP+7AA (124±4 mmHg) treatment prevented this increase. At 10 wks, MAP was elevated in RUPP vs NP (133±5 vs. 120±5 mmHg, p=0.08), with a significant decrease in MAP in RUPP+7AA (107±6 mmHg) vs. RUPP (p<0.05). Total circulating NK cells were increased in RUPP vs NP (45±9. vs. 29± 8% gated cells, ns), which was prevented in RUPP+7AA (19±16 % gated cells) at 8 wks PP. Hearts were enlarged with RUPP vs NP (0.41±0.04 vs. 0.36±0.02g/100gBW, ns), which was normalized in RUPP+7AA (0.34±0.02g/100gBW). Previous studies show that during pregnancy complex IV is significantly lower along with a decrease mt function in RUPP vs NP. Complex IV mt proteins in the heart were elevated in RUPP+7AA vs. RUPP (5.5±1.7 vs. 3.0±0.2 AU, ns). Conclusion: In summary, PP PE rats have an increase in MAP, NK cells, and larger hearts. AT1-AA inhibition restores complex IV mt levels and improves HTN, immune activation, and cardiac hypertrophy PP. This study highlights the importance of AT1-AA inhibition during PE to prevent CVD later in life. Supported: AHA18CDA34110264
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