Abstract
The liver plays an important role in cardiovascular disease by amplifying systemic inflammation, while the underlying mechanisms remain to be defined. Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme, and pharmacological inhibition of sEH was shown to protect against various inflammatory diseases. In this study, we have identified a novel role of the liver, through expression of sEH, in the pathogenesis of abdominal aortic aneurysm (AAA). sEH expression and activity were markedly higher in mouse liver compared with aorta and further increased in the context of AAA. Pharmacological inhibition or hepatocyte-specific disruption of sEH prevented AAA formation in two animal models of AAA (angiotensin II infusion and aortic calcium chloride application in male mice), concomitant with reduced expression of complement C3 and serum amyloid A, liver-derived inflammatory factors causally linked to AAA formation. Interestingly, data from co-incubation of liver ex vivo with aorta identified galectin-3 secreted from the aneurysm-prone aorta that activates sEH in the liver. We also determined 12,13-dihydroxyoctadecenoic acid (DiHOME) and various circulating pro-inflammatory cytokines as a downstream mechanism potentially associated with hepatic sEH in the context of AAA. These novel findings provide direct evidence that bidirectional crosstalk between aorta and liver contributes to AAA via hepatic sEH.
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Data availability
Datasets analyzed in this study are available from the corresponding authors upon reasonable request. Specific data underlying each Figure is noted in Figure Legends and Supplementary Data file. The LC-MS/MS proteomics data have been deposited to the ProteomeXchange Consortium via the Proteomics Identification database (PRIDE) partner repository with the dataset identifier PXD073197.
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Acknowledgements
This study was funded by grants AG076235 (NIH), 971459 (AHA), 863622 (AHA), R35 ES030443 (NIH/NIEHS RIVER award), and P42 ES004699 (NIH/NIEHS Superfund Research Program).
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H.W.K. and N.L.W. conceived and designed research, D.S.K., T.H., M.O., B.G., H.S., P.V., R.C., N.C., M.M., R.P., S.C., T.W.B., R.H., G.A., H.G.S., M.S., S.H. W.Z., and P.C. performed experiments, D.S.K., T.H., M.O, B.G., P.V., R.C., N.C., N.L.W., and H.W.K. analyzed data, D.J.F, G.C., Y.H., X.L., R.L., A.G., L.Y., D.C.Z., S.H.H., B.D.H., N.L.W., and H.W.K. interpreted results of experiments, N.L.W. and H.W.K. wrote manuscript, D.J.F., R.L., S.H.H., B.D.H., N.L.W., and H.W.K. edit and revised manuscript, N.L.W. and H.W.K. approved final version of manuscript.
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Kim, D.S., Horimatsu, T., Ogbi, M. et al. Soluble epoxide hydrolase in the liver orchestrates abdominal aortic aneurysm formation in mice. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09765-x
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DOI: https://doi.org/10.1038/s42003-026-09765-x
