RT Journal Article
SR 00
ID 10.1161/HYPERTENSIONAHA.115.05544
A1 Menni, Cristina
A1 Graham, Delyth
A1 Kastenmuller, Gabi
A1 Alharbi, Nora H.J.
A1 Alsanos, Safaa Md
A1 McBride, Martin
A1 Mangino, Massimo
A1 Titcombe, Philip
A1 Shin, So-Youn
A1 Psatha, Maria
A1 Geisendorfer, Thomas
A1 Huber, Anja
A1 Peters, Annette
A1 Wang-Sattler, Rui
A1 Xu, Tao
A1 Brosnan, Mary Julia
A1 Trimmer, Jeff
A1 Reichel, Christian
A1 Mohney, Robert P.
A1 Soranzo, Nicole
A1 Edwards, Mark H.
A1 Cooper, Cyrus
A1 Church, Alistair C.
A1 Suhre, Karsten
A1 Gieger, Christian
A1 Dominiczak, Anna F.
A1 Spector, Tim D.
A1 Padmanabhan, Sandosh
A1 Valdes, Ana M.
T1 Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate
JF Hypertension
YR 2015
FD 2015-08
VO 66
SP 422
OP 429
AB 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 [SBP]: β [95% confidence interval], 1.31 [0.83–1.78], P=6.81×10−8; diastolic BP [DBP]: 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.
PB American Heart Association
SN 0194-911X
LK https://eprints.gla.ac.uk/107096/