Foetal hypoxia increases cardiac AT(2)R expression and subsequent vulnerability to adult ischaemic injury.

AIMS Hypoxia is a common stress to the foetus and results in increased cardiac vulnerability to adult ischaemic injury. This study tested the hypothesis that foetal hypoxia causes programming of increased AT(2) receptor (AT(2)R) expression in the heart, resulting in the heightened cardiac susceptibility to adult ischaemic injury. METHODS AND RESULTS Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O(2) from days 15 to 21 of gestation) groups. Hypoxia resulted in significantly increased AT(2)R in the heart of adult offspring. Multiple glucocorticoid response elements (GREs) were identified at the AT(2)R promoter, deletion of which increased the promoter activity. Consistently, ex vivo treatment of isolated foetal hearts with dexamethasone for 48 h decreased AT(2)R expression, which was inhibited by RU 486. Hypoxia decreased glucocorticoid receptors (GRs) in the hearts of foetal, 3-week-old and 3-month-old offspring, resulting in decreased GR binding to the GREs at the AT(2)R promoter. The inhibition of AT(2)R improved postischaemic recovery of left ventricular function and rescued the foetal hypoxia-induced cardiac ischaemic vulnerability in male adult animals. In contrast, the inhibition of AT(1) receptors decreased the postischaemic recovery. CONCLUSION The results demonstrate that in utero hypoxia causes programming of increased AT(2)R gene expression in the heart by downregulating GR, which contributes to the increased cardiac vulnerability to adult ischaemic injury caused by prenatal hypoxic exposure.