Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy

Panigrahy, D.; Kelly, A.; Wang, W.; Yang, J.; Hwang, S. H.; Gillespie, M.; Howard, I.; Bueno-Beti, C.; Asimaki, A.; Penna, V.; Lavine, K.; Edin, M.; Zeldin, D.; Hammock, B.; Saffitz, J.

doi:10.1101/2024.02.17.580812

bioRxiv · 10.1101/2024.02.17.580812

Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy

Panigrahy, D.·Kelly, A.·Wang, W.·Yang, J.·Hwang, S. H.·Gillespie, M.·Howard, I.·Bueno-Beti, C.·Asimaki, A.·Penna, V.·Lavine, K.·Edin, M.·Zeldin, D.·Hammock, B.·Saffitz, J.

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Abstract

Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro- inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.

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Panigrahy, D., Kelly, A., Wang, W., Yang, J., Hwang, S. H., Gillespie, M., Howard, I., Bueno-Beti, C., Asimaki, A., Penna, V., Lavine, K., Edin, M., Zeldin, D., Hammock, B., Saffitz, J.. 2024-02-19. Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy. https://doi.org/10.1101/2024.02.17.580812

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