title: Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB.
abstract: Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca(2+)/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rose
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bond
authors.forename: Scott
authors.initials: S
authors.lastname: Tighe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Toth
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Wellman
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Briso de Montiano
authors.forename: Martin M
authors.initials: MM
authors.lastname: Lewinter
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lounsbury
mesh_terms: D000465:Algorithms; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002536:Cerebral Arteries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006973:Hypertension / Q000139:chemically induced* / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D012313:RNA; D048049:Extracellular Signal-Regulated MAP Kinases