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Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring.

ABSTRACT: In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal 'priming' of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine model of obesity-induced glucose dysregulated pregnancy, we demonstrate that NRF2 activation by maternal sulforaphane (SFN) supplementation normalizes NRF2-linked NQO1, GCL and CuZnSOD expression in maternal and fetal liver placental and fetal heart tissue by gestational day 17.5. Activation of NRF2 in utero in wild type but not NRF2 deficient mice improved markers of placental efficiency and partially restored fetal growth. SFN supplementation was associated with reduced markers of fetal cardiac oxidative stress, including Nox2 and 3-nitrotyrosine, as well as attenuation of cardiac mass and cardiomyocyte area in male offspring by postnatal day 52 and improved vascular function in male and female offspring by postnatal day 98. Our findings are the first to highlight the functional consequences of NRF2 modulation in utero on early-life cardiovascular function in offspring, demonstrating that activation of NRF2 affords cardiovascular protection in offspring of pregnancies affected by redox dysregulation.

SUBMITTER: Psefteli PM

PROVIDER: S-EPMC10534264 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring.

Psefteli Paraskevi-Maria PM Morris Jessica K JK Ehler Elisabeth E Smith Lorna L Bowe James J Mann Giovanni E GE Taylor Paul D PD Chapple Sarah J SJ

Redox biology 20230918

In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal 'priming' of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine ...[more]

PMID: 37774548

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Project description:Background: One of the severely debilitating and fatal subtypes of hemorrhagic stroke is intracerebral hemorrhage (ICH), which lacks an adequate cure at present. The Zhilong Huoxue Tongyu (ZLHXTY) capsule has been utilized effectively since last decade to treat ICH, in some provinces of China but the scientific basis for its mechanism is lacking. Purpose: To investigate the neuroprotective role of ZLHXTY capsules for ICH-induced oxidative injury through the regulation of redox imbalance with the Nrf2 signaling pathway. Methods: Autologous blood injection model of ICH in C57BL/6J mice was employed. Three treatment groups received ZLHXTY once daily through oral gavage at doses 0.35 g/kg, 0.7 g/kg, and 1.4 g/kg, started after 2 h and continued for 72 h of ICH induction. The neurological outcome was measured using a balance beam test. Serum was tested for inflammatory markers IL-1β, IL-6, and TNF-α through ELISA, oxidative stress through hydrogen peroxide content assay, and antioxidant status by total antioxidant capacity (T-AOC) assay. Nuclear extract from brain tissue was assayed for Nrf2 transcriptional factor activity. RT-qPCR was performed for Nfe2l2, Sod1, Hmox1, Nqo1, and Mgst1; and Western blotting for determination of protein expression of Nrf2, p62, Pp62, Keap, HO1, and NQO1. Fluoro-jade C staining was also used to examine neuronal damage. Results: ZLHXTY capsule treatment following ICH demonstrated a protective effect against oxidative brain injury. Neurological scoring showed improvement in behavioral outcomes. ELISA-based identification demonstrated a significant decline in the expression of serum inflammatory markers. Hydrogen peroxide content in serum was found to be reduced. The total antioxidant capacity was also reduced in serum, but the ZLHXTY extract showed a concentration-dependent increase in T-AOC speculating at its intrinsic antioxidant potential. Nrf2 transcriptional factor activity, mRNA and protein expression analyses revealed normalization of Nrf2 and its downstream targets, which were previously elevated as a result of oxidative stress induced by ICH. Neuronal damage was also reduced markedly after ZLHXTY treatment as revealed by Fluoro-jade C staining. Conclusion: ZLHXTY capsules possess an intrinsic antioxidant potential that can modulate the ICH-induced redox imbalance in the brain as revealed by the normalization of Nrf2 and its downstream antioxidant targets.

Dataset Information

Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring.

Publications

Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring.

Similar Datasets

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