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 [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

The DnaK homologue of the marine Vibrio sp. strain S14 binds to the unprocessed form of a carbon starvation-specific periplasmic protein

The Escherichia coli DnaK homoiogue in Vibrio sp. strain S14 was shown to possess chaperone function for translocation during carbon starvation. This was demonstrated by using the method of co‐immunoprecipitation. DnaK co‐precipitated with the carbon starvation‐specific periplasmic space protein Csp5 three hours after the onset of carbon starvation. Pulse‐chasing of the protein with radiolabelled methlonine followed by the addition of an excess of unlabelled methionine demonstrated that the Csp5 protein was translocated across the inner membrane. Only the cytoplasmic unprocessed precursor form of Csp5 co‐precipitated with DnaK. The non‐covalent binding between the two proteins was found to be ATP‐dependent, as the addition of ATP released the interaction between DnaK and the precursor form of Csp5, as was shown both on silver‐stained SDS‐poly‐acrylamide gels and by Western blot analysis. We suggest that DnaK maintains the carbon starvatlon‐Inducible protein Csp5 in a translocation‐competent form In the cytoplasm. Copyright © 1994, Wiley Blackwell. All rights reserve

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