Foetal hypoxia increases cardiac AT2R expression and subsequent vulnerability to adult ischaemic injury

AimsHypoxia 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 AT2 receptor (AT2R) expression in the heart, resulting in the heightened cardiac susceptibility to adult ischaemic injury. Methods and resultsTime-dated pregnant rats were divided between normoxic and hypoxic (10.5 O2 from days 15 to 21 of gestation) groups. Hypoxia resulted in significantly increased AT2R in the heart of adult offspring. Multiple glucocorticoid response elements (GREs) were identified at the AT2R promoter, deletion of which increased the promoter activity. Consistently, ex vivo treatment of isolated foetal hearts with dexamethasone for 48 h decreased AT2R 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 AT2R promoter. The inhibition of AT2R 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 AT1 receptors decreased the postischaemic recovery. ConclusionThe results demonstrate that in utero hypoxia causes programming of increased AT2R gene expression in the heart by downregulating GR, which contributes to the increased cardiac vulnerability to adult ischaemic injury caused by prenatal hypoxic exposure. © 2010 The Author.