Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation.
The endothelin-converting enzyme (ECE)-1 gene is a candidate for human blood pressure (BP) regulation and we report the identification of the new gene variants T-839G, C-338A, L75F, A677V and C+295T. Transient transfection of the reporter constructs containing the -338A allele showed an increase in promoter activity compared with the wild-type promoter. EMSA revealed the specific binding of E2F-2 to both ECE-1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F-2 compared with -338C. The clinical relevance of this finding was analyzed in 704 hypertensive patients. In untreated hypertensive women, both the -338A and -839G alleles were significantly associated with ambulatory BP values. This study provides the first evidence of a link between the cell-cycle-associated E2F family and BP regulation via a component of the endothelin system.
Funke-Kaiser
Heiko
H
Institute of Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany.
Reichenberger
Florian
F
Köpke
Karla
K
Herrmann
Stefan-Martin
SM
Pfeifer
Jacqueline
J
Orzechowski
Hans-Dieter
HD
Zidek
Walter
W
Paul
Martin
M
Brand
Eva
E
D000328:Adult; D000368:Aged; D000483:Alleles; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D050703:E2F2 Transcription Factor; D000072396:Endothelin-Converting Enzymes; D005260:Female; D017930:Genes, Reporter; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008666:Metalloendopeptidases; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D050703:E2F2 Transcription Factor; D014157:Transcription Factors; D004247:DNA; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes