title: Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.
abstract: Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual's lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc-/- mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc-/- mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc-/- mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene-based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12-15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.
authors: Institute of Experimental and Clinical Pharmacology and Toxicology and Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors: Nadine
authors: N
authors: Beetz
authors: Michael D
authors: MD
authors: Harrison
authors: Marc
authors: M
authors: Brede
authors: Xiangang
authors: X
authors: Zong
authors: Michal J
authors: MJ
authors: Urbanski
authors: Anika
authors: A
authors: Sietmann
authors: Jennifer
authors: J
authors: Kaufling
authors: Stefan
authors: S
authors: Lorkowski
authors: Michel
authors: M
authors: Barrot
authors: Mathias W
authors: MW
authors: Seeliger
authors: Maria Augusta
authors: MA
authors: Vieira-Coelho
authors: Pavel
authors: P
authors: Hamet
authors: Daniel
authors: D
authors: Gaudet
authors: Ondrej
authors: O
authors: Seda
authors: Johanne
authors: J
authors: Tremblay
authors: Theodore A
authors: TA
authors: Kotchen
authors: Mary
authors: M
authors: Kaldunski
authors: Rolf
authors: R
authors: Nüsing
authors: Bela
authors: B
authors: Szabo
authors: Howard J
authors: HJ
authors: Jacob
authors: Allen W
authors: AW
authors: Cowley
authors: Martin
authors: M
authors: Biel
authors: Monika
authors: M
authors: Stoll
authors: Martin J
authors: MJ
authors: Lohse
authors: Ulrich
authors: U
authors: Broeckel
authors: Lutz
authors: L
authors: Hein
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000235:genetics; D004837:Epinephrine / Q000502:physiology; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008955:Models, Cardiovascular; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009490:Neurosecretory Systems / Q000503:physiopathology; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D013312:Stress, Physiological; D013564:Sympathetic Nervous System / Q000503:physiopathology*
chemical_list: D005136:Eye Proteins; D020555:GTP-Binding Protein Regulators; D010750:Phosphoproteins; C065631:phosducin; D004247:DNA; D004837:Epinephrine