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

AbstractWomen 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.

Download Full-text

Angiotensin II Type 1 Receptor Agonistic Autoantibody Blockade Improves Postpartum Hypertension and Cardiac Mitochondrial Function in Rat Model of Preeclampsia

10.21203/rs.3.rs-638411/v1 ◽

2021 ◽

Author(s):

George W. Booz ◽

Daniel Kennedy ◽

Michael Bowling ◽

Taprieka Robinson ◽

Daniel Azubuike ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Rat Model ◽

Mitochondrial Function ◽

Type I ◽

Sprague Dawley ◽

Long Term Effects ◽

Amino Acid Peptide ◽

Uterine Perfusion

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 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.

Download Full-text

Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00179.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. R256-R262 ◽

Cited By ~ 6

Author(s):

Venkata Ramana Vaka ◽

Mark W. Cunningham ◽

Evangeline Deer ◽

Michael Franks ◽

Tarek Ibrahim ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Angiotensin Ii ◽

Rat Model ◽

Mitochondrial Respiration ◽

Umbilical Vein ◽

Type I ◽

Sprague Dawley ◽

Mitochondrial Oxidative Stress ◽

Umbilical Vein Endothelial Cells

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.

Download Full-text

Rat model of long term effects after fractionated (2Gy/day) 60Gy irradiation of rat liver

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1331934 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

F Moriconi ◽

IA Malik ◽

A Amanzada ◽

G Ramadori ◽

CF Hess

Keyword(s):

Rat Liver ◽

Rat Model ◽

Long Term Effects

Download Full-text

Rat model of fractionated (2 Gy/day) 60 Gy irradiation of the liver: long-term effects

Zeitschrift für Gastroenterologie ◽

10.1055/s-0033-1352735 ◽

2013 ◽

Vol 51 (08) ◽

Author(s):

M Rave-Fränk ◽

I Malik ◽

H Christiansen ◽

S Sultan ◽

N Naz ◽

...

Keyword(s):

Rat Model ◽

Long Term Effects

Download Full-text

Long-term effects (>24 months) of multiple lifestyle intervention on major cardiovascular risk factors among high risk subjects: a meta-analysis

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.253 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

H Bergum ◽

I Sandven ◽

TO Klemsdal

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Risk ◽

Systolic Blood Pressure ◽

Total Cholesterol ◽

Cardiovascular Risk Factors ◽

Lifestyle Intervention ◽

Small Study ◽

Long Term Effects

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Norwegian health department Background The evidence of the long-term effects of multiple lifestyle intervention on cardiovascular risk is uncertain. We aimed to summarize the evidence from randomized clinical trials examining the efficacy of lifestyle intervention on major cardiovascular risk factors in subjects at high cardiovascular risk. Methods Eligible trials investigated the impact of lifestyle intervention versus usual care with minimum 24 months follow-up, reporting more than one major cardiovascular risk factor. A literature search updated April 15, 2020 identified 12 eligible studies. The results from individual trials were combined using fixed and random effect models, using the standardized mean difference (SMD) to estimate effect sizes. Small-study effect was evaluated, and heterogeneity between studies examined by subgroup and meta-regression analyses considering patient- and study-level variables. Results Small-study effect was not identified. Lifestyle intervention reduced systolic blood pressure modestly with an estimated SMD of -0.13, 95% confidence interval (CI): -0.21 to -0.04, with moderate heterogeneity (I² = 59%), corresponding to a mean difference of approximately 2 mmHg (MD = -1.86, 95% CI: -3.14 to -0.57, p = 0.0046). This effect disappeared in the subgroup of trials judged at low risk of bias (SMD = 0.02, 95% CI: -0.08 to 0.11). For the outcome total cholesterol SMD was -0.06, 95% CI: -0.13 to 0.00, with no heterogeneity (I² = 0%), indicating no effect of the intervention. Conclusion Lifestyle intervention resulted in only a modest effect on systolic blood pressure and no effect on total cholesterol after 24 months. Further lifestyle trials should consider the challenge of maintaining larger long-term benefits to ensure impact on cardiovascular outcomes.

Download Full-text

The long-term bio-behavioural effects of juvenile sildenafil treatment in Sprague-Dawley versus Flinders Sensitive Line rats

Acta Neuropsychiatrica ◽

10.1017/neu.2021.4 ◽

2021 ◽

pp. 1-20

Author(s):

Juandré Lambertus Bernardus Saayman ◽

Stephanus Frederik Steyn ◽

Christiaan Beyers Brink

Keyword(s):

Sprague Dawley ◽

Long Term Effects ◽

Bdnf Level ◽

Treatment Groups ◽

Sd Rats ◽

Behavioural Effects ◽

Sensitive Line ◽

Level Analysis ◽

Flinders Sensitive Line

Abstract Objective: To investigate the long-term effects of juvenile sub-chronic sildenafil (SIL) treatment on the depressive-like behaviour and hippocampal brain-derived neurotrophic factor (BDNF) levels of adult Sprague-Dawley (SD) versus Flinders Sensitive Line (FSL) rats. Methods: SD and FSL rats were divided into pre-pubertal and pubertal groups, whereafter 14-day saline or SIL treatment was initiated. Pre-pubertal and pubertal rats were treated from postnatal day 21 (PND21) and PND35, respectively. The open field and forced swim tests (FST) were performed on PND60, followed by hippocampal BDNF level analysis one day later. Results: FSL rats displayed greater immobility in the FST compared to SD rats (p < 0.0001), which was reduced by SIL (p < 0.0001), regardless of treatment period. Hippocampal BDNF levels were unaltered by SIL in all treatment groups (p > 0.05). Conclusion: Juvenile sub-chronic SIL treatment reduces the risk of depressive-like behaviour manifesting during young adulthood in genetically susceptible rats.

Download Full-text