title: Norepinephrine causes epigenetic repression of PKCε gene in rodent hearts by activating Nox1-dependent reactive oxygen species production.
abstract: Heart disease is the leading cause of death in the United States. Recent studies demonstrate that fetal programming of PKCε gene repression results in ischemia-sensitive phenotype in the heart. The present study tests the hypothesis that increased norepinephrine causes epigenetic repression of PKCε 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 PKCε promoter methylation at Egr-1 and Sp-1 binding sites, leading to PKCε gene repression. N-acetylcysteine, diphenyleneiodonium, and apocynin blocked norepinephrine-induced ROS production and the promoter methylation, and also restored PKCε 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 PKCε 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 PKCε 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.
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Fuxia
authors.initials: F
authors.lastname: Xiong
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005318:Fetal Heart / Q000187:drug effects* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D009638:Norepinephrine / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D051744:Protein Kinase C-epsilon; D009638:Norepinephrine