Abstract 046: Cardiac Mitochondria are Impaired After Transient Neonatal High Oxygen Exposure in a Rat Model of Prematurity-Related Condition

Abstract

The heart relies on adequate mitochondrial (mito) ATP production to match myocardial demand, mostly through oxidative phosphorylation. Preterm birth (PT) results in ex utero development of an immature myocardium and PT-born individuals represent a newly recognized group at high risk of cardiovascular diseases. Our group has shown that newborn rats exposed to high oxygen (O 2 ), mimicking PT-related conditions, develop O 2 -induced cardiomyopathy (OIC) and dysfunction later in life. However, whether mito impairments prevail in the programmed left ventricle (LV) changes associated with PT is unknown. We aimed to determine whether OIC is associated with altered LV mito characteristics in 4 wks-old rats. Male rat pups were kept with their mother in 80% O 2 (OIC) or room air (Ctrl) from days 3 to 10 of life. Results are mean±SEM; OIC vs. Ctrl are compared using t-test (n=4/group.P<0.05). At 4 wks, extracellular flux analysis of isolated LV cardiomyocytes revealed significantly decreased O 2 consumption rate in OIC (12.14±5.74 vs. 67.39±13.61 pmoles/min/ug). OIC rats show reduced LV mito copy number determined by the ratio between mito and genomic DNA (26.7±6.30 vs. 52.7±7.32), biogenesis markers Pgc1α (0.59±0.14 vs. 1.18±0.25), and citrate synthase (0.20±0.16 vs. 1.60±0.56) mRNA, and reduced Complex IV (0.66±0.15 vs. 1.26±0.09) protein expression. Gene expression (RT-PCR) of key glycolytic enzymes, hexokinase (3.34±0.59 vs. 0.88±0.39) and glucose-6-phosphate dehydrogenase (2.85±0.48 vs. 0.58±0.08) is significantly increased, indicating a shift toward glycolysis. OIC also were found to have higher LV mtROS production (7581±51 vs. 5191±99, fluorescence arbitrary units) and decreased antioxidant SOD2 protein expression (0.84±0.09 vs. 1.04±0.05). Taken together our results indicate that neonatal hyperoxia exposure leads to decreased LV mito biogenesis and function with impaired oxidative phosphorylation capacity in juvenile animals. Further studies are needed to determine the role of long-term mito dysfunction in the increased susceptibility to heart failure observed after deleterious neonatal conditions.