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. Rodent studies show that exposure to hyperoxia in early postnatal life causes heart failure later in life that resembles heart failure in humans who were born preterm. Neonatal hyperoxia exposure affected 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. While 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 DNA repair and growth arrest genes 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 hyperoxia exposed mice. 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. C57BL/6J mice purchased from the Jackson Laboratories were used to generate newborn pups that were exposed to room air (21% oxygen) or hyperoxia (100% oxygen) between birth and postnatal day (PND) 4. The mice were then sacrificed by injecting with avertin and the thorax was exposed. The hearts were removed, and the left atria and ventricles were carefully separated with forceps and a tungsten needle. The separated atria and ventricle were used to isolate genomic DNA free RNA using the RNeasy plus kit (Qiagen, 74134). There were 4 experimental conditions with 5 individual mice in each group. The 4 experimental conditions are room air left atria (RA_LA), room air left ventricle (RA_LV), hyperoxia left atria (O2_LA), and hyperoxia left ventricle (O2_LV) where the number after LA or LV represents one of the five individual mice in that experimental group.