Faculty Collaboration Database

Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice. J Clin Invest 2009 Dec;119(12):3597-3612

Date

12/05/2009

Pubmed ID

19959875

Pubmed Central ID

PMC2786789

DOI

10.1172/JCI38433

Scopus ID

2-s2.0-72849116579 (requires institutional sign-in at Scopus site)   39 Citations

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.

Author List

Beetz N, Harrison MD, Brede M, Zong X, Urbanski MJ, Sietmann A, Kaufling J, Lorkowski S, Barrot M, Seeliger MW, Vieira-Coelho MA, Hamet P, Gaudet D, Seda O, Tremblay J, Kotchen TA, Kaldunski M, Nüsing R, Szabo B, Jacob HJ, Cowley AW Jr, Biel M, Stoll M, Lohse MJ, Broeckel U, Hein L

Authors

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin
Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Alleles
Amino Acid Sequence
Animals
Base Sequence
Blood Pressure
DNA
Epinephrine
Eye Proteins
Female
GTP-Binding Protein Regulators
Homozygote
Humans
Hypertension
In Vitro Techniques
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Models, Cardiovascular
Models, Molecular
Molecular Sequence Data
Neurosecretory Systems
Phenotype
Phosphoproteins
Polymorphism, Single Nucleotide
Stress, Physiological
Sympathetic Nervous System