期刊
FASEB JOURNAL
卷 26, 期 7, 页码 2753-2763出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-199422
关键词
ischemic heart disease; sympathetic activity; oxidative stress; promoter methylation
资金
- U.S. National Institutes of Health [HL82779, HL83966, HL110125, DA032510]
- California Tobacco-Related Disease Research Program [18KT-0024]
Heart disease is the leading cause of death in the United States. Recent studies demonstrate that fetal programming of PKC epsilon gene repression results in ischemia-sensitive phenotype in the heart. The present study tests the hypothesis that increased norepinephrine causes epigenetic repression of PKC epsilon gene in the heart via Nox1-dependent reactive oxygen species (ROS) production. Prolonged norepinephrine treatment increased ROS production in fetal rat hearts and embryonic ventricular myocyte H9c2 cells via a selective increase in Nox1 expression. Norepinephrine-induced ROS resulted in an increase in PKC epsilon promoter methylation at Egr-1 and Sp-1 binding sites, leading to PKC epsilon gene repression. N-acetylcysteine, diphenyleneiodonium, and apocynin blocked norepinephrine-induced ROS production and the promoter methylation, and also restored PKC epsilon mRNA and protein to control levels in vivo in fetal hearts and in vitro in embryonic myocyte cells. Accordingly, norepinephrine-induced ROS production, promoter methylation, and PKC epsilon gene repression were completely abrogated by knockdown of Nox1 in cardiomyocytes. These findings provide evidence of a novel interaction between elevated norepinephrine and epigenetic repression of PKC epsilon gene in the heart mediated by Nox1-dependent oxidative stress and suggest new insights of molecular mechanisms linking the heightened sympathetic activity to aberrant cardioprotection and increased ischemic vulnerability in the heart.-Xiong, F., Xiao, D., Zhang, L. Norepinephrine causes epigenetic repression of PKC epsilon gene in rodent hearts by activating Nox1-dependent reactive oxygen species production. FASEB J. 26, 2753-2763 (2012). www.fasebj.org
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