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

ABSTRACT: 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.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.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.

SUBMITTER: Xue Q

PROVIDER: S-EPMC3020132 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Xue Qin Q Dasgupta Chiranjib C Chen Man M Zhang Lubo L

Cardiovascular research 20100923 2

<h4>Aims</h4>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.<h4>Methods and results</h4>Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O(2) from days 15 to 21 of gestation) groups. Hypoxia resul ...[more]

PMID: 20870653

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Project description:Aimsthe adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it.Methods and resultsadult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL(+) and 15.0±2.5% were AO(+). At the 30-day (d) time point myocardial cell death was back to baseline (n?=?3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3(+) and 7.4±0.6% were PCNA(+) (n?=?3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n?=?12 at each time point).Conclusionszebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models.

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

Publications

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

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