Placental treatment improves cardiac tolerance to ischemia/reperfusion insult in adult male and female offspring exposed to prenatal hypoxia

Hula, Nataliia; Spaans, Floor; Vu, Jennie; Quon, Anita; Kirschenman, Raven; Cooke, Christy‐Lynn M.; Phillips, Tom J.; Case, C. P.; Davidge, Sandra T.

doi:10.1016/j.phrs.2021.105461

Cited by 14 publications

(19 citation statements)

References 45 publications

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“…8 Offspring of hypoxic pregnancies display cardiac abnormalities in adulthood and appear to be sensitized to ischemia/reperfusion injury. 7,[9][10][11][12][13][14][15][16][17] These findings support epidemiological evidence from human pregnancies, which show hypoxia during development can increase the risk of cardiac dysfunction in offspring. [18][19][20][21][22][23] Combined, evidence derived from human clinical studies and from experimental preclinical models strongly supports that fetal hypoxia is an independent risk factor for offspring cardiovascular disease.…”

Section: Introductionsupporting

confidence: 84%

“…However, in the longer term, gestational hypoxia can overwhelm this circulatory protection, and lead to impaired cardiac development, 4–6 thickening of the aortic wall, 7 and reduced cardiac output in the fetus 8 . Offspring of hypoxic pregnancies display cardiac abnormalities in adulthood and appear to be sensitized to ischemia/reperfusion injury 7,9–17 . These findings support epidemiological evidence from human pregnancies, which show hypoxia during development can increase the risk of cardiac dysfunction in offspring 18–23 .…”

Section: Introductionsupporting

confidence: 58%

“…From each litter, two hearts were used for mitochondrial analysis in separate chambers (one heart per chamber) and two hearts were snap frozen in liquid nitrogen and stored at −80°C for future analysis. For each set of experiments, pups were used from the same position on the uterine horn to account for the potential differential exposure to hypoxia within the uterus 12 . Tail tips were collected and stored at −20°C for sex determination by SRY genotyping.…”

Section: Methodsmentioning

confidence: 99%

“…For each set of experiments, pups were used from the same position on the uterine horn to account for the potential differential exposure to hypoxia within the uterus. 12 Tail tips were collected and stored at −20°C for sex determination by SRY genotyping. A schematic of the hypoxia model is shown in Figure 1.…”

Section: Hypoxia Modelmentioning

confidence: 99%

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Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

Smith

Swiderska

Lock

et al. 2022

Journal of Pineal Research

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Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6–20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H2O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain (p < .01) and increased placental weight (p < .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) (p < .05), and an increase in H2O2 production/O2 consumption (p < .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionsupporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Hypoxia Modelmentioning

confidence: 99%

See 2 more Smart Citations

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

Smith

Swiderska

Lock

et al. 2022

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…Increasing evidence validated the theory of fetal origins of adult disease and that development of cardiovascular disease in adulthood might be associated with intrauterine insults ( 2 – 4 ). A study in rats revealed that antenatal hypoxia could also increase the severity of heart damage after ischemia-reperfusion injury in offspring ( 5 ). However, the underlying mechanism of the pathogenesis of impaired cardiovascular function is still controversial and unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Liu

Luo

Liao

et al. 2022

Front. Cardiovasc. Med.

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Intrauterine hypoxia is a common complication during pregnancy and could increase the risk of cardiovascular disease in offspring. However, the underlying mechanism is controversial. Memantine, an NMDA receptor antagonist, is reported to be a potential cardio-protective agent. We hypothesized that antenatal memantine treatment could prevent heart injury in neonatal offspring exposed to intrauterine hypoxia. Pregnant rats were exposed to gestational hypoxia or antenatal memantine treatment during late pregnancy. Newborns were then sacrificed to assess multiple parameters. The results revealed that Intrauterine hypoxia resulted in declining birth weight, heart weight, and an abnormally high heart weight/birth weight ratio. Furthermore, intrauterine hypoxia caused mitochondrial structural, functional abnormalities and decreased expression of DRP1, and upregulation of NMDAR1 in vivo. Antenatal memantine treatment,an NMDARs antagonist, improved these changes. In vitro, hypoxia increased the glutamate concentration and expression of NMDAR1. NMDAR activation may lead to similar changes in mitochondrial function, structure, and downregulation of DRP1 in vitro. Pharmacological blockade of NMDARs by the non-competitive NMDA antagonist MK-801 or knockdown of the glutamate receptor NR1 significantly attenuated the increased mitochondrial reactive oxygen species and calcium overload-induced by hypoxia exposure. These facts suggest that memantine could provide a novel and promising treatment for clinical use in intrauterine hypoxia during pregnancy to protect the cardiac mitochondrial function in the offspring. To our best knowledge, our research is the first study that shows intrauterine hypoxia can excessively activate cardiac NMDARs and thus cause mitochondrial dysfunction.

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Alkaloid leonurine exerts anti‐inflammatory effects via modulating MST1 expression in trophoblast cells

Zong

Zhao

2021

Immunity Inflam & Disease

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Background: Pre-eclampsia (PE) is mainly attributed to the inflammation of trophoblast cells in pregnant women, which results in damage to the maternal organs and growth retardation of the fetus. Alkaloid leonurine (LNR) is a plant compound and has anti-inflammatory effects. Here we aimed to investigate the effects of LNR on human and mouse trophoblast cells and the underlying mechanisms. Methods: The levels of the inflammatory factors in trophoblast cells under lipopolysaccharides (LPS) stimulation were analyzed with ELISA. Western blot was employed to examine the protein expression. Trophoblast cells in Mammalian ste20-like kinase 1 (MST1 −/− ) or wild type (WT) mice were isolated to examine the expression of signal molecules in the nuclear factor-κB (NF-κB) pathway. Concentration-dependent activity of NF-κB was examined.The regulation of LNR and MST1 in MST1 −/− trophoblast cells was studied as well.Results: Our data showed that LNR exhibited anti-inflammatory effects and suppressed the NF-κB signaling by inhibiting LPS-induced inflammation in trophoblast cells. LNR upregulated the expression of MST1, and the antiinflammatory role of LNR was greatly relieved in MST1-knockout trophoblast cells, although it displayed weak roles in NF-κB signaling.Conclusion: LNR exhibits anti-inflammatory effects on human and mouse trophoblast cells by upregulating MST1 in the NF-κB signal pathway.

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Placental treatment improves cardiac tolerance to ischemia/reperfusion insult in adult male and female offspring exposed to prenatal hypoxia

Cited by 14 publications

References 45 publications

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Alkaloid leonurine exerts anti‐inflammatory effects via modulating MST1 expression in trophoblast cells

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