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

Daniela Ravizzoni Dartora, Adrien Flahault, Carolina N R Pontes, Ying He, Alyson Deprez, Anik Cloutier, Gaël Cagnone, Perrine Gaub, Gabriel Altit, Jean-Luc Bigras, Jean-Sébastien Joyal, Thuy Mai Luu, Yan Burelle, Anne Monique Nuyt, Daniela Ravizzoni Dartora, Adrien Flahault, Carolina N R Pontes, Ying He, Alyson Deprez, Anik Cloutier, Gaël Cagnone, Perrine Gaub, Gabriel Altit, Jean-Luc Bigras, Jean-Sébastien Joyal, Thuy Mai Luu, Yan Burelle, Anne Monique Nuyt

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% 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.

Keywords: cardiomyopathies; humanin; hyperoxia; mitochondria; premature birth.

Figures

Figure 1.
Figure 1.
Mitochondrial ultrastructure, morphology, and integrity in left ventricle cardiac muscle. Electron microscope images of left ventricular fibers (A) from rats exposed only to room air (control) and rats exposed to hyperoxia as newborns (oxygen-induced cardiomyopathy [OIC]). Top views were magnified ×2900 and bottom views ×7000. Individual mitochondria are indicated by arrows. Mitochondrial average surface area (B), perimeter (C), proportion (%) of cardiomyocyte area covered by mitochondria (D), and frequency distribution of mitochondrial size (E) all showed lower values for the OIC group than for controls. F presents the distribution (%) of mitochondria according to integrity score (0–4). Data shown are mean±SEM (SEM); n=3/group. *P<0.05, **P<0.01, ****P<0.0001 comparing control vs OIC with unpaired t test.
Figure 2.
Figure 2.
Mitochondrial respiration in isolated mitochondria from left ventricle cardiac muscle. Rates of oxygen consumption in isolated left ventricular mitochondria from rats exposed only to room air (control) and rats exposed to hyperoxia as newborns (oxygen-induced cardiomyopathy [OIC]). Values are shown at metabolic state 2 (A); metabolic state 3 (B) metabolic state 4 (C); and uncoupled respiration, using carbonyl cyanide-4- (trifluoromethoxy)phenylhydrazone (FCCP; D). Respiratory control ratio (RCR) indicates functional integrity of mitochondria (E). Data shown are mean±SEM; n=9/group. *P<0.05 comparing control vs OIC with unpaired t test.
Figure 3.
Figure 3.
Glycolysis activation and lipid deposition in left ventricle cardiac tissue.A, Representative blot and histogram of compiled data of the protein HIF (hypoxia-inducible factor)-1α expression in rats exposed only to room air (control) and rats exposed to hyperoxia as newborns (oxygen-induced cardiomyopathy [OIC]); β-tubulin was used as internal standard. Hexokinase 1 mRNA (B) and hexokinase 2 mRNA (C) are expressed relative to the 40S ribosomal protein S16 (S16). Representative image (D) and quantification (E) of intracardiac lipid deposition in left ventricle sections. Scale bar: 36.8 µm Data shown are mean±SEM; n=6/group. Lipid droplets appear as green fluorescent dots in the representative images. *P<0.05; ***P<0.001 comparing control vs OIC with unpaired t test.
Figure 4.
Figure 4.
Mitochondrial biogenesis and abundance, mitochondrial superoxide production, SOD2 (superoxide dismutase 2), and Nrf2 (nuclear factor erythroid 2–related factor) expression in cardiac left ventricle. Markers of mitochondrial biogenesis and abundance in left ventricle tissue from rats exposed only to room air (control) and rats exposed to hyperoxia as newborns (oxygen-induced cardiomyopathy [OIC]): Pgc (peroxisome proliferator-activated receptor gamma coactivator)-1α gene expression (A), citrate synthase (B), the ratio of mitochondrial DNA (mtDNA) to genomic DNA (gDNA; C) were all reduced in rats with OIC compared with controls. Mitochondrial superoxide production was increased in isolated left ventricular cardiomyocytes from OIC rats as compared to room air (control); representative images and quantification (D). SOD2 protein expression (representative blot with β-tubulin as internal standard and histograms of compiled data) is shown in (E) and Nrf2 gene expression in (F) in left ventricle. Gene mRNA expression are expressed relative to the 40S ribosomal protein S16 (S16). Data shown are mean±SEM; n=6/group. *P<0.05, **P<0.01 comparing control vs OIC with unpaired t test.
Figure 5.
Figure 5.
Clinical study: humanin levels and left ventricle (LV) ejection fraction in young adults born preterm vs full-term. Serum humanin levels in young adults born preterm (<30 wk’ gestation) and full-term (≥37 wk’ gestation; A). LV ejection fraction in preterm (B) and full-term groups (C) and peak global longitudinal strain (%) in preterm (D) and full-term groups (E) by humanin tertile. Tertiles: low (≤130 pg/mL), medium (131–193 pg/mL), high (>193 pg/mL). Statistical tests: Mann-Whitney U (A) and Kendall (B and C).

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