title: A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids.
abstract: Depressed calcium handling by the sarcoplasmic reticulum (SR) Ca-ATPase and its regulator phospholamban (PLN) is a key characteristic of human and experimental heart failure. Accumulating evidence indicates that increases in the relative levels of PLN to Ca-ATPase in failing hearts and resulting inhibition of Ca sequestration during diastole, impairs contractility. Here, we identified a genetic variant in the PLN promoter region, which increases its expression and may serve as a genetic modifier in dilated cardiomyopathy (DCM). The variant AF177763.1:g.203A>C (at position -36 bp relative to the PLN transcriptional start site) was found only in the heterozygous form in 1 out of 296 normal subjects and in 22 out of 381 cardiomyopathy patients (heart failure at age of 18-44 years, ejection fraction=22+/-9%). In vitro analysis, using luciferase as a reporter gene in rat neonatal cardiomyocytes, indicated that the PLN-variant increased activity by 24% compared to the wild type. Furthermore, the g.203A>C substitution altered the specific sequence of the steroid receptor for the glucocorticoid nuclear receptor (GR)/transcription factor in the PLN promoter, resulting in enhanced binding to the mutated DNA site. These findings suggest that the g.203A>C genetic variant in the human PLN promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267-0575, USA.
authors.forename: Kobra
authors.initials: K
authors.lastname: Haghighi
authors.forename: Guoli
authors.initials: G
authors.lastname: Chen
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sato
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Suiwen
authors.initials: S
authors.lastname: He
authors.forename: Fotis
authors.initials: F
authors.lastname: Kolokathis
authors.forename: Luke
authors.initials: L
authors.lastname: Pater
authors.forename: Ioannis
authors.initials: I
authors.lastname: Paraskevaidis
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Dimitrios Th
authors.initials: DT
authors.lastname: Kremastinos
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics*; D004247:DNA; D017931:DNA Primers; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic / Q000187:drug effects*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D004247:DNA; D017931:DNA Primers; D005938:Glucocorticoids; D000099211:Phospholamban