Fetal programming of the cardiac mitochondrial permeability transition pore in male offspring from hypoxic pregnancies

A lack of oxygen during fetal development (fetal hypoxia) permanently alters the structure and function of the heart, leading to increased susceptibility to ischemia reperfusion (IR) injury in adulthood. However, the underlying cellular mechanisms are incompletely understood. In this study, we used a rat model to understand the role of calcium, reactive oxygen species and the mitochondrial permeability transition pore (MPTP) in programming IR sensitivity in offspring from hypoxic pregnancies. Pregnant Wistar rats were subjected to either ambient oxygen (∼21 %) throughout gestation, 13 % oxygen from gestational day 6-20, or 10.5 % oxygen from gestational day 15-20 (rat term ∼ 22 days). Offspring were raised to adulthood and hearts were subjected to ex vivo IR injury during Langendorff perfusion, whilst measuring ventricular pressure, intracellular calcium, oxidative stress and NAD(P)H autofluorescence. In addition, calcium retention capacity (CRC) and MPTP components were measured in isolated mitochondria, as well as basal H₂O₂ emission and electron transport system activity. Exposure to fetal hypoxia (10.5 % oxygen) increased IR sensitivity in adult offspring, demonstrated by increased diastolic pressure (p < 0.05), lipid peroxidation (p < 0.05), and an increased rate of NAD(P)H oxidation (p < 0.05) at reperfusion. This increased sensitivity to IR was associated with a decreased CRC (p < 0.01), increased basal H₂O₂ emission (p < 0.05) and decreased basal respiratory capacity linked to complex IV (p < 0.01). Additionally, both models of fetal hypoxia (13 % and 10.5 %) increased the abundance of the MPTP regulatory protein cyclophilin D in adult hearts (p < 0.01 and <0.001, respectively). Together, these data suggest that exposure to hypoxia during fetal development can programme MPTP calcium sensitivity by altering factors that modulate the pore (e.g. H₂O₂ emission, electron transport system activity, NAD(P)H oxidation and CypD content). These data could help to explain why individuals from hypoxic pregnancies are more susceptible to myocardial infarction, and other cardiovascular diseases.