Cardiac Left Ventricle Mitochondrial Dysfunction After Neonatal Exposure to Hyperoxia: Relevance for Cardiomyopathy After Preterm Birth

Abstract

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% O 2 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.

S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice

“…The consistent underlying mechanism behind these protective effects involves the modulation of oxidative stress. For instance, a study utilizing a rat model of preterm birth demonstrated significant alterations in the structure and function of the cardiac left ventricle mitochondria following transient neonatal exposure to hyperoxia [ 29 ]. These alterations encompassed a reduction in mitochondrial size and integrity, along with a subsequent decline in oxidative phosphorylation capacity later in life.…”

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency

“…It is therefore possible that these long-term effects of cysteine deficiency-and to a lesser extent, vitamin C deficiency-in the neonatal period could increase the risk of pulmonary conditions such asthma and chronic obstructive pulmonary disease. Indeed, preterm neonates that go through neonatal oxidative stress often develop these conditions at adulthood [1][2][3][4][5][6][7][8][9][10][11]. Future studies should focus on the effect of these neonatal deficiencies on the development of chronic lung diseases in adulthood.…”

“…Very premature birth (≤32 weeks of gestation) is associated with several short-and long-term consequences over the development of several diseases. In neonatal life, infants born prematurely develop complications such as bronchopulmonary dysplasia [1], and they are at higher risk of developing asthma, chronic obstructive pulmonary disease (COPD) and other respiratory complications in adulthood [2,3], as well as other complications [1,2,[4][5][6][7][8][9][10][11]. Despite the strong clinical evidence, it is challenging to seize what specific aspects of prematurity lead to the increased risk of neonatal and adult diseases.…”

Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases

“…Hyperoxia can also induce cardiac injury. Rats exposed to hyperoxia exhibit decreased oxidative phosphorylation and increased markers of glycolysis in the muscle tissue of the left ventricle [ 85 ]. Cohen et al found that hyperoxia reduced fatty acid synthesis in atrial cardiomyocytes, leading to inhibited cell proliferation and survival [ 86 ].…”