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2015 ; 66
(2
): 422-9
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Metabolomic identification of a novel pathway of blood pressure regulation
involving hexadecanedioate
#MMPMID26034203
Menni C
; Graham D
; Kastenmüller G
; Alharbi NH
; Alsanosi SM
; McBride M
; Mangino M
; Titcombe P
; Shin SY
; Psatha M
; Geisendorfer T
; Huber A
; Peters A
; Wang-Sattler R
; Xu T
; Brosnan MJ
; Trimmer J
; Reichel C
; Mohney RP
; Soranzo N
; Edwards MH
; Cooper C
; Church AC
; Suhre K
; Gieger C
; Dominiczak AF
; Spector TD
; Padmanabhan S
; Valdes AM
Hypertension
2015[Aug]; 66
(2
): 422-9
PMID26034203
show ga
High blood pressure is a major contributor to the global burden of disease and
discovering novel causal pathways of blood pressure regulation has been
challenging. We tested blood pressure associations with 280 fasting blood
metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality
was performed on significant independent metabolites (P<8.9×10(-5)). Replication
was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515).
Three independent animal experiments were performed to establish causality: (1)
blood pressure change after increasing circulating metabolite levels in
Wistar-Kyoto rats; (2) circulating metabolite change after salt-induced blood
pressure elevation in spontaneously hypertensive stroke-prone rats; and (3)
mesenteric artery response to noradrenaline and carbachol in metabolite treated
and control rats. Of the15 metabolites that showed an independent significant
association with blood pressure, only hexadecanedioate, a dicarboxylic acid,
showed concordant association with blood pressure (systolic BP: ? [95% confidence
interval], 1.31 [0.83-1.78], P=6.81×10(-8); diastolic BP: 0.81 [0.5-1.11],
P=2.96×10(-7)) and mortality (hazard ratio [95% confidence interval], 1.49
[1.08-2.05]; P=0.02) in TwinsUK. The blood pressure association was replicated in
KORA and Hertfordshire. In the animal experiments, we showed that oral
hexadecanedioate increased both circulating hexadecanedioate and blood pressure
in Wistar-Kyoto rats, whereas blood pressure elevation with oral sodium chloride
in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity
to noradrenaline was significantly increased in mesenteric resistance arteries
from hexadecanedioate-treated rats compared with controls, indicated by the shift
to the left of the concentration-response curve (P=0.013). Relaxation to
carbachol did not show any difference. Our findings indicate that
hexadecanedioate is causally associated with blood pressure regulation through a
novel pathway that merits further investigation.
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