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Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate

Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate
Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate
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.
blood pressure, fatty acid synthases, hypertension metabolomics, mortality
0194-911X
422-429
Menni, C.
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Graham, D.
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Kastenmuller, G.
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Alharbi, N.H.
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Alsanosi, S.M.
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McBride, M.
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Mangino, M.
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Titcombe, P.
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Shin, S.Y.
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Psatha, M.
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Geisendorfer, T.
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Huber, A.
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Peters, A.
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Wang-Sattler, R.
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Xu, T.
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Brosnan, M.J.
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Trimmer, J.
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Reichel, C.
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Mohney, R.P.
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Soranzo, N.
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Edwards, M.H.
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Cooper, C.
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Church, A.C.
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Suhre, K.
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Gieger, C.
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Dominiczak, A.F.
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Spector, T.D.
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Padmanabhan, S.
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Valdes, A.M.
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Menni, C.
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Graham, D.
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Kastenmuller, G.
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Alharbi, N.H.
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Alsanosi, S.M.
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McBride, M.
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Mangino, M.
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Titcombe, P.
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Shin, S.Y.
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Psatha, M.
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Geisendorfer, T.
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Huber, A.
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Peters, A.
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Wang-Sattler, R.
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Xu, T.
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Brosnan, M.J.
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Trimmer, J.
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Reichel, C.
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Mohney, R.P.
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Soranzo, N.
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Edwards, M.H.
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Cooper, C.
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Church, A.C.
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Suhre, K.
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Gieger, C.
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Dominiczak, A.F.
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Spector, T.D.
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Padmanabhan, S.
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Valdes, A.M.
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Menni, C., Graham, D., Kastenmuller, G., Alharbi, N.H., Alsanosi, S.M., McBride, M., Mangino, M., Titcombe, P., Shin, S.Y., Psatha, M., Geisendorfer, T., Huber, A., Peters, A., Wang-Sattler, R., Xu, T., Brosnan, M.J., Trimmer, J., Reichel, C., Mohney, R.P., Soranzo, N., Edwards, M.H., Cooper, C., Church, A.C., Suhre, K., Gieger, C., Dominiczak, A.F., Spector, T.D., Padmanabhan, S. and Valdes, A.M. (2015) Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate. Hypertension, 66 (2), 422-429. (doi:10.1161/HYPERTENSIONAHA.115.05544). (PMID:26034203)

Record type: Article

Abstract

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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More information

Accepted/In Press date: 27 April 2015
e-pub ahead of print date: 1 June 2015
Keywords: blood pressure, fatty acid synthases, hypertension metabolomics, mortality
Organisations: MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 379231
URI: http://eprints.soton.ac.uk/id/eprint/379231
ISSN: 0194-911X
PURE UUID: f02e8aaf-8025-4059-81ce-e267eb947d94
ORCID for P. Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for C. Cooper: ORCID iD orcid.org/0000-0003-3510-0709

Catalogue record

Date deposited: 21 Jul 2015 13:55
Last modified: 08 Jan 2022 03:21

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Contributors

Author: C. Menni
Author: D. Graham
Author: G. Kastenmuller
Author: N.H. Alharbi
Author: S.M. Alsanosi
Author: M. McBride
Author: M. Mangino
Author: P. Titcombe ORCID iD
Author: S.Y. Shin
Author: M. Psatha
Author: T. Geisendorfer
Author: A. Huber
Author: A. Peters
Author: R. Wang-Sattler
Author: T. Xu
Author: M.J. Brosnan
Author: J. Trimmer
Author: C. Reichel
Author: R.P. Mohney
Author: N. Soranzo
Author: M.H. Edwards
Author: C. Cooper ORCID iD
Author: A.C. Church
Author: K. Suhre
Author: C. Gieger
Author: A.F. Dominiczak
Author: T.D. Spector
Author: S. Padmanabhan
Author: A.M. Valdes

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