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A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Perinatal Inflammation Results in Sex-Dependent Cardiac Dysfunction
Leeann R Pavlek1,2, Kathryn M Heyob1, Nitya R Jacob1
1Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, USA.
Insights
Early life inflammation and oxygen exposure can alter cardiac proteins, leading to heart dysfunction in adult mice. These changes, particularly in males, suggest a potential predictor for heart disease risk in human infants.
Area of Science:
- Cardiovascular Biology
- Neonatal Physiology
- Developmental Origins of Health and Disease
Background:
- Preterm birth and fetal growth restriction are linked to adult heart failure.
- Adverse maternal environments contribute to poor fetal development and preterm birth.
- Neonatal hyperoxia is often required for premature infants with immature lungs.
Purpose of the Study:
- To test if early-life cardiac structural protein changes predict adult cardiac dysfunction.
- To investigate sex-dependent differences in cardiac adaptation to early-life insults.
Main Methods:
- Utilized a murine model of maternal inflammation (lipopolysaccharide) and neonatal hyperoxia.
- Assessed cardiac structural proteins (alpha-myosin heavy chain) and left ventricular function.
- Examined sex-specific pathological changes at 10 months of age.
Main Results:
- Female mice showed transient decreases in alpha-myosin heavy chain (αMHC) expression post-inflammation.
- Male mice exposed to inflammation and hyperoxia exhibited delayed but significant increases in αMHC.
- Left ventricular function correlated with protein changes, with males displaying a more severe cardiac phenotype.
Conclusions:
- Early alterations in cardiac contractile proteins are temporally linked to cardiac dysfunction.
- Male mice demonstrated a more severe sex-dependent cardiac adaptation.
- Findings suggest potential predictive value for heart disease risk in growth-restricted human infants.
Background:
An increased incidence of adult-onset heart failure is seen in individuals born preterm or affected by fetal growth restriction. An adverse maternal environment is associated with both preterm birth and poor fetal development, and postnatal oxygen therapy is frequently required to sustain oxygenation of vulnerable tissues due to lung immaturity.
Methods:
Studies using our murine model of maternal inflammation (LPS) and neonatal hyperoxia exposure (O2) observed pathological changes in cardiac structural proteins and functional analysis with sex dependent differences in pathologies at 10 months of age. Using our previous model, the current investigations tested the hypothesis that early-life perturbations in cardiac structural proteins might predict adult cardiac dysfunction in a sex dependent manner.
Results:
LPS-exposed females had lower αMHC mRNA and protein at P0 and P7 relative to the saline-exposed females, but these changes did not persist. Male mice exposed to LPS/O2 had normal expression of αMHC mRNA and protein compared to saline/room air controls though P56, when they dramatically increased. Correlative changes were observed in left ventricular function with a more severe phenotype in the males indicating sex-based differences in cardiac adaptation.
Conclusions:
Our findings demonstrate that early changes in contractile proteins temporally correlate with deficits in cardiac contractility, with a more severe phenotype in males. Our data suggest that similar findings in humans may predict risk for disease in growth-restricted infants.
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