Whole genome transcriptomics reveal distinct atrial versus ventricular responses to neonatal hyperoxia.

Preterm infants exposed to supplemental oxygen (hyperoxia) are at risk for developing heart failure later in life. Exposing rodents in early postnatal life to hyperoxia causes heart failure that resembles cardiac disease seen in adult humans who were born preterm. Neonatal hyperoxia exposure affects the left atrium and left ventricle differently, inhibiting the proliferation and survival of atrial cardiomyocytes while enhancing cardiomyocyte differentiation in the ventricle. In this study, whole genome transcriptomics revealed the left atria of neonatal mice are more responsive to hyperoxia than the left ventricle, with the expression of 4,285 genes affected in the atrium and 1,743 in the ventricle. Although hyperoxia activated p53 target genes in both chambers, it caused greater DNA damage, phosphorylation of the DNA damage responsive ataxia-telangiectasia mutated (ATM) kinase, mitochondrial stress, and apoptosis in the atrium. In contrast, hyperoxia induced the expression of genes involved in DNA repair and stress granules in the ventricle. Atrial cells also showed a greater loss of extracellular matrix and superoxide dismutase 3 (SOD3) expression, possibly contributing to the enlargement of the left atrium and reduced velocity of blood flow across the mitral valve seen in mice exposed to hyperoxia. Diastolic dysfunction and heart failure in hyperoxia-exposed mice may thus stem from its effects on the left atrium, suggesting chamber-specific therapies may be needed to address diastolic dysfunction and heart failure in people who were born preterm.