Eicosanoid Inflammatory Mediators Are Robustly Associated With Blood Pressure in the General Population

Abstract

Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid–derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin‐angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti‐inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography–mass spectrometry, we profiled 545 distinct high‐quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP ( P <Bonferroni‐corrected threshold of 0.05/545). We used forward selection linear regression modeling in FINRISK to define a general formula for individual eicosanoid risk score. Individuals of the top risk score quartile in FINRISK had a 9.0 (95% CI, 8.0–10.1) mm Hg higher systolic BP compared with individuals in the lowest quartile in fully adjusted models. Observed metabolite associations were consistent across FINRISK and FHS. Conclusions Plasma eicosanoids demonstrate strong associations with BP in the general population. As eicosanoid compounds affect numerous physiological processes that are central to BP regulation, they may offer new insights about the pathogenesis of hypertension, as well as serve as potential targets for therapeutic intervention.

A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes – a prospective study in three independent cohorts

“…We speculate that 8-iso-PGA1 and 12-HHTrE could be used as personalized biomarkers in the identification of people at risk of developing type 2 diabetes. Interestingly, the latter metabolite was also associated with hypertension in our recent analysis [36]. Better understanding of determinants and functions of these two eicosanoids may allow for a more targeted approach in the preventive measures such as lifestyle and medical interventions [3,4].…”

“…The second known eicosanoid demonstrating a positive independent association with incident type 2 diabetes is 12-HHTrE. Different enantiomers of 12-HHTrE are metabolites of nonenzymatic activity as well as of COX-and LOX-pathways, and they have been implicated in conditions such as breast cancer, hypertension, endothelial prostacyclin formation, response to acute exercise and high carbohydrate intake [35,36,37,38].…”

A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes: a prospective study in three independent cohorts

“…A study using the same mass spectrometry platform recently found 12-HHTrE to be robustly associated with blood pressure 36. None of the eicosanoids associated with blood pressure were correlated with 8-iso-PGA1, however one of them (Tetranor-12(R)-HETE) strongly correlated with 12-HHTrE.…”

“…The second known eicosanoid demonstrating a positive independent association with incident type 2 diabetes is 12-HHTrE. Different enantiomers of 12-HHTrE are metabolites of non-enzymatic activity as well as of COX and LOX pathways, and they have been implicated in conditions such as breast cancer, hypertension, endothelial prostacyclin formation, response to acute exercise and high carbohydrate intake 35–38…”

The clinical translation of eicosanoids and other oxylipins, although challenging, should be actively pursued

“…Several large lipidomic studies have recently highlighted this potential. For instance, untargeted oxylipin profiling in large cohort studies, namely FINRISK 2002 and the Framingham Heart Study, identified and validated a strong association between free oxylipins in plasma and blood pressure in the general population [9] .

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