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Published on: February 13, 2019
Cardiac Left Ventricle Mitochondrial Dysfunction After Neonatal Exposure to Hyperoxia: Relevance for Cardiomyopathy
Daniela Ravizzoni Dartora1, Adrien Flahault1, Carolina N R Pontes1,2
1Department of Pediatrics, Sainte-Justine University Hospital (Centre Hospitalier Universitaire Sainte-Justine) and Research Centre (D.R.D., A.F., C.N.R.P., Y.H., A.D., A.C., G.C., P.G., J.-L.B., J.-S.J., T.M.L., A.M.N.), Faculty of Medicine, University of Montreal, Quebec, Canada.
Insights
Neonatal hyperoxia, mimicking preterm birth, damages heart mitochondria in juvenile rats. Preterm adults show lower humanin levels, suggesting a link to adult cardiac changes.
Area of Science:
- Cardiology
- Neonatology
- Mitochondrial Biology
Background:
- Preterm birth is linked to left ventricle dysfunction and increased heart disease risk.
- The exact mechanisms of heart disease post-preterm birth remain unclear.
- Mitochondrial dysfunction is a key factor in cardiomyopathy and heart failure.
Purpose of the Study:
- To investigate if neonatal hyperoxia in rats induces left ventricle mitochondrial changes.
- To determine if humanin levels are reduced in young adults born preterm.
Main Methods:
- Rat pups exposed to 80% oxygen (hyperoxia) or room air (control) from postnatal days 3-10.
- Left ventricle mitochondrial structure and function assessed in 4-week-old male rats.
- Circulating humanin levels measured in a cohort of preterm and term-born young adults.
Main Results:
- Oxygen-exposed rats exhibited smaller mitochondria, impaired oxidative phosphorylation, and increased glycolysis.
- Mitochondria in oxygen-exposed rats showed reduced biogenesis, lipid deposits, and increased superoxide production.
- Preterm adults had lower serum humanin levels, associated with cardiac function metrics.
Conclusions:
- Neonatal hyperoxia impairs left ventricle mitochondrial structure and function in juvenile rats.
- Reduced serum humanin levels observed in preterm adults.
- Preterm birth conditions may lead to persistent left ventricle mitochondrial alterations into adulthood.
Background:
Individuals born preterm present left ventricle changes and increased risk of cardiac diseases and heart failure. The pathophysiology of heart disease after preterm birth is incompletely understood. Mitochondria dysfunction is a hallmark of cardiomyopathy resulting in heart failure. We hypothesized that neonatal hyperoxia in rats, a recognized model simulating preterm birth conditions and resulting in oxygen-induced cardiomyopathy, induce left ventricle mitochondrial changes in juvenile rats. We also hypothesized that humanin, a mitochondrial-derived peptide, would be reduced in young adults born preterm.
Methods:
Sprague-Dawley pups were exposed to room air (controls) or 80% O2 at postnatal days 3 to 10 (oxygen-induced cardiomyopathy). We studied left ventricle mitochondrial changes in 4 weeks old males. In a cohort of young adults born preterm (n=55) and age-matched term (n=54), we compared circulating levels of humanin.
Results:
Compared with controls, oxygen-exposed rats showed smaller left ventricle mitochondria with disrupted integrity on electron microscopy, decreased oxidative phosphorylation, increased glycolysis markers, and reduced mitochondrial biogenesis and abundance. In oxygen-exposed rats, we observed lipid deposits, increased superoxide production (isolated cardiomyocytes), and reduced Nrf2 gene expression. In the cohort, left ventricle ejection fraction and peak global longitudinal strain were similar between groups however humanin levels were lower in preterm and associated with left ventricle ejection fraction and peak global longitudinal strain.
Conclusions:
In conclusion, neonatal hyperoxia impaired left ventricle mitochondrial structure and function in juvenile animals. Serum humanin level was reduced in preterm adults. This study suggests that preterm birth-related conditions entail left ventricle mitochondrial alterations that may underlie cardiac changes perpetuated into adulthood. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03261609.
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