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Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of angiotensin II receptors.

Abstract：

BACKGROUND AND PURPOSE:Maternal cigarette smoking increases the risk of neonatal morbidity. We tested the hypothesis that perinatal nicotine exposure causes heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through aberrant expression patterns of angiotensin II type 1 (AT(1)R) and type 2 (AT(2)R) receptors in the developing brain. METHODS:Nicotine was administered to pregnant rats through subcutaneous osmotic minipumps. HI brain injury was determined in 10-day-old pups. AT(1)R and AT(2)R expression patterns were assessed through Western blotting, quantitative polymerase chain reaction, immunofluorescence, and confocal imaging. RESULTS:Perinatal nicotine exposure significantly increased HI brain infarct size in male, but not female, pups. In fetal brains, nicotine caused a decrease in mRNA and protein abundance of AT(2)R but not AT(1)R. The downregulation of AT(2)R persisted in brains of male pups, and nicotine treatment resulted in a significant increase in methylation of CpG locus 3 bases upstream of TATA-box at the AT(2)R gene promoter. In female brains, there was an increase in AT(2)R but a decrease in AT(1)R expression. Both AT(1)R and AT(2)R expressed in neurons but not in astrocytes in the cortex and hippocampus. Central application of AT(1)R antagonist losartan or AT(2)R antagonist PD123319 increased HI brain infarct size in both male and female pups. In male pups, AT(2)R agonist CGP42112 abrogated nicotine-induced increase in HI brain infarction. In females, PD123319 uncovered the nicotine's effect on HI brain infarction. CONCLUSIONS:Perinatal nicotine exposure causes epigenetic repression of the AT(2)R gene in the developing brain resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex-dependent manner.

journal_name

Stroke

journal_title

Stroke

authors

Li Y,Xiao D,Dasgupta C,Xiong F,Tong W,Yang S,Zhang L

doi

10.1161/STROKEAHA.112.664698

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

2483-90

issue

eissn

0039-2499

issn

1524-4628

pii

STROKEAHA.112.664698

journal_volume

pub_type

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Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of angiotensin II receptors.