Abstract

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 Dsg2mut/mut 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 Dsg2mut/mut 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.