P0743 - Long-term Cardiopulmonary Effects of Neonatal Intermittent Hypoxia Exposure

Background:
Accumulating evidence suggests that adult preterm survivors exhibit increased Cardiopulmonary risk. Preterm infants exposed to high oxygen concentrations often exhibit hypoxemic episodes. Previously, we showed that neonatal mice exposed to intermittent hypoxic episodes superimposed on hyperoxia exhibit lung mitochondrial DNA damage and cardiopulmonary dysfunction. But whether this dysfunction persists in adulthood is less explored.

Objective:
To determine whether adult mice exposed to neonatal intermittent hypoxic episodes exhibit persistent cardiopulmonary impairment.
Design/

Methods:
Neonatal mice (N=50) were randomized to the following groups for 21 days: Normoxia (RA); Hyperoxia (O2 65%); Hyperoxia cycling with intermittent hypoxia (HYP+IH) and Normoxia cycling with intermittent hypoxia (RA+IH). After day 21, animals remained in RA
until 3 months of age. Pulmonary hypertension and cardiac function was assessed by echocardiography. Right ventricular hypertrophy was assessed by the weight ratio of the right ventricle to left ventricle + septum (RV/LV+S). Lung angiogenesis was assessed by lung vascular density. Mitochondrial DNA damage, content and copy number was assessed by PCR. Mitochondrial PINK1, PARKIN, UPC-2, LC3B and Beclin protein expression were assessed by Western Blot. Data are expressed as mean ±SD and analyzed by ANOVA.

Results:
Exposure of adult mice to neonatal IH significantly decreased vascular density (Table 1). PAT/PET, MV E/A and TV E/A ratios were however not significantly different between the groups (Table 1). As compared to the RA group, lung mitochondrial DNA content and copy number was significantly increased in the HYP and IH groups and there was a trend for a significant increase in mitochondrial DNA damage in these groups (Fig. 1A). In order to ascertain whether these mitochondrial DNA alterations in the HYP and IH groups was secondary to impaired mitophagy, the expression of PINK1, PARKIN, UPC-2, LC3B and Beclin was assessed. There was no difference in PINK1 or Beclin expression between the groups. In contrast, lung mitochondrial LC3B I/II was significantly increased in the HYP+IH group as compared to the RA group (Fig. 1B).
Conclusion(s):
Against our hypothesis, neonatal IH did not impair cardiopulmonary function in adulthood. However, neonatal HYP + IH impaired mitophagy and persistently impaired lung angiogenesis into adulthood. We speculate that adult preterm survivors exposed to neonatal IH may have increased cardiovascular risk secondary to persistent impairment in mitochondrial function.