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.
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