Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy
We analyzed the role of pro- and anti-inflammatory eicosanoids in the pathogenesis of arrhythmogenic cardiomyopathy (ACM). Lipidomics revealed reduced levels of anti-inflammatory oxylipins in plasma and increased levels of pro-inflammatory eicosanoids in hearts of Dsg2<sup>mut/mut</sup> mice, a preclinical model of ACM. Disease features were reversed in vitro in rat ventricular myocytes expressing mutant JUP by the anti-inflammatory epoxyeicosatrienoic acid 14-15-EET, whereas 14,15-EEZE, which antagonizes the 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that converts anti-inflammatory EETs into polar, less active diols, prevented progression of myocardial injury in Dsg2<sup>mut/mut</sup> mice and promoted recovery of contractile function. This was associated with reduced myocardial expression of genes involved in innate immune signaling and fewer injurious macrophages expressing CCR2. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM. Inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.
Authors
- Jun Yang (ORCID: https://orcid.org/0000-0001-8126-1728)
- Kory J. Lavine (ORCID: https://orcid.org/0000-0003-1948-9945)
- Angeliki Asimaki (ORCID: https://orcid.org/0000-0001-9886-6870)
- Carlos Bueno‐Betí (ORCID: https://orcid.org/0000-0003-4626-1276)
- Darryl C. Zeldin (ORCID: https://orcid.org/0000-0002-2087-7307)
- Vinay Penna (ORCID: https://orcid.org/0000-0002-9082-7874)
- Michael Allen Gillespie
- Isabella Howard (ORCID: https://orcid.org/0000-0001-8292-4693)
- Abigail Kelly
- Sung Hee Hwang (ORCID: https://orcid.org/0000-0002-9891-928X)
- Weicang Wang (ORCID: https://orcid.org/0000-0002-2722-507X)
- Katherine Quinlivan
- Jeffrey E. Saffitz
- Dipak Panigrahy
- Matthew L Edin
- Bruce D. Hammock
Institutions
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- St George's, University of London (GB)
- Washington University in St. Louis (US)
- Triangle (US)
- National Institute of Environmental Health Sciences (US)
- Genomics (United Kingdom) (GB)
- University of California, Davis (US)
Publication Details
- Journal
- JACC Basic to Translational Science
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1016/j.jacbts.2024.12.010
- Citations
- 4
- Primary Topic
- Cardiovascular Effects of Exercise
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- Beth Israel Deaconess Medical Center
- Florida State University
- Washington University in St. Louis
- University of California, Davis
- St. George's, University of London
- National Institute of Environmental Health Sciences