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<p>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.</p><p></p>

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Soluble epoxide hydrolase in the liver orchestrates abdominal aortic aneurysm formation in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • David S. Kim,
  • Tetsuo Horimatsu,
  • Mourad Ogbi,
  • Brandee Goo,
  • Hong Shi,
  • Praneet Veerapaneni,
  • Ronnie Chouhaita,
  • Nicole Cyriac,
  • Mary Moses,
  • Rosaria Prasad,
  • Stephen Cave,
  • Tyler W. Benson,
  • Ragheb Harb,
  • Ghaith Aboud,
  • Hunter G. Sellers,
  • Mitchell Shivers,
  • Stephen Haigh,
  • David J. Fulton,
  • Gábor Csányi,
  • Yuqing Huo,
  • Xiaochun Long,
  • Philip Coffey,
  • Richard Lee,
  • Avirup Guha,
  • Wenbo Zhi,
  • Lufei Young,
  • Darryl C. Zeldin,
  • Sung Hee Hwang,
  • Bruce D. Hammock,
  • Neal L. Weintraub,
  • Ha Won Kim

摘要

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.