Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.
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.
Beetz
Nadine
N
Institute of Experimental and Clinical Pharmacology and Toxicology and Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Harrison
Michael D
MD
Brede
Marc
M
Zong
Xiangang
X
Urbanski
Michal J
MJ
Sietmann
Anika
A
Kaufling
Jennifer
J
Lorkowski
Stefan
S
Barrot
Michel
M
Seeliger
Mathias W
MW
Vieira-Coelho
Maria Augusta
MA
Hamet
Pavel
P
Gaudet
Daniel
D
Seda
Ondrej
O
Tremblay
Johanne
J
Kotchen
Theodore A
TA
Kaldunski
Mary
M
Nüsing
Rolf
R
Szabo
Bela
B
Jacob
Howard J
HJ
Cowley
Allen W
AW
Biel
Martin
M
Stoll
Monika
M
Lohse
Martin J
MJ
Broeckel
Ulrich
U
Hein
Lutz
L
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*
D005136:Eye Proteins; D020555:GTP-Binding Protein Regulators; D010750:Phosphoproteins; C065631:phosducin; D004247:DNA; D004837:Epinephrine