title: Foetal hypoxia increases cardiac AT(2)R expression and subsequent vulnerability to adult ischaemic injury.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Fetal Origin Diseases, First Hospital of Soochow University, Suzhou 215000, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xue
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000367:Age Factors; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005311:Fetal Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D005938:Glucocorticoids; D006727:Hormone Antagonists; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011965:Receptors, Glucocorticoid; C073402:PD 123319; D015735:Mifepristone; D003907:Dexamethasone