182 - Sex-dependent Expression of miR195 Regulated Sirtuin (Sirt)1 in Varying Oxygen Concentrations of Hyperoxia-induced Experimental Bronchopulmonary Dysplasia (BPD)

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 182
Publication Number: 182.403

Nicole Melchiorre, Cooper Medical School of Rowan University, Sicklerville, NJ, United States; Pragnya Das, Cooper Medical School of Rowan University, Camden, NJ, United States; Varsha Machatt. Prahaladan, Cooper University Health Care, Philadelphia, PA, United States; Xander T. Takada, Rowan University, Sewell, NJ, United States; Vineet Bhandari, The Children's Regional Hospital at Cooper, Camden, NJ, United States

Presenting Author(s)

Nicole Melchiorre (she/her/hers)

Medical Student
Cooper Medical School of Rowan University
Sicklerville, New Jersey, United States

Background: Hyperoxia is a key contributor to the pathogenesis of BPD, the most common chronic lung disease in preterm infants. We identified miR195 as a novel miRNA targeting Sirt1 in BPD. Sirt1, an anti-inflammatory protein, is a metabolic NAD(+) dependent protein/histone deacetylase that regulates proinflammatory mediators. As BPD is an inflammatory condition and Sirt1 is expressed in the lungs, we believe miR195 regulates the expression of Sirt1, following hyperoxic injury in the lungs.

Objective: To evaluate the expression of miR195 regulated Sirt1 pathway in the developing lungs of neonatal mouse male and female pups exposed to varying O₂ concentrations in the hyperoxia-induced experimental BPD model.

Design/Methods: Newborn mouse pups (P0 at saccular stage, males and females) were exposed to mild (40%), moderate (60%) and severe (100%) O₂for 4d (till P4 at alveolar stage) followed by recovery in room air (RA) for 10d (till P14) after which they were sacrificed and their lungs harvested to quantify the expression of miR195 by Q-PCR and Sirt1 by western blotting.

Results: There was no difference in the expression of miR195 in RA males or females. However, in mild and moderate injury, miR195 was significantly upregulated in males (P< 0.05/P< 0.005), respectively. In females, it was significantly upregulated at 60% (P< 0.005), but not at 40% or 100%. Interestingly, BPD females had a much higher miR195 expression at 100% (P< 0.05), was significantly downregulated at 40% (P< 0.05), while there was no change at 60%, when compared to BPD males. The upregulation was dramatic in females when the injury was increased from 40% to 60% (P< 0.0001) (Fig. 1A). The expression of Sirt1 protein, (a known direct downstream target of miR195) was significantly downregulated at 100% in males, but females had a higher expression at 100%. A similar opposing effect was also seen at 60% BPD, with males showing the maximum upregulation at 60%, while in females, it was downregulated. In 40% BPD, although not statistically significant, females showed a trend towards a Sirt1 increase (Figs. 1B, C).

Conclusion(s): It is well established that BPD males have a worse prognosis than females and overexpression of Sirt1 is protective. Our preliminary findings show that females fare better in severe hyperoxia, as compared to males. We believe that the high expression of Sirt1 in 60% BPD in males, as compared to females, might be an adaptive effect to the increasing hyperoxic environment, while females in a similar environment have already adapted possibly by other mechanistic pathways.