Epoxyeicosatrienoic acids and sEH inhibition prevent cardiac dysfunction in CVB3-induced myocarditis by positively regulating type I interferon signaling

Myocarditis is a challenging inflammatory disease of the heart and better understanding of its etiology is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by cytochrome P450 enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus (CVB3)-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and, in the murine heart, and correlated with the increased expression and activity of the sEH after CVB3 infection. Administration of a sEH inhibitor prevented CVB3-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated vial infection/ improved viral resistance by activating type I interferon (IFN) signaling. At the molecular level, EETs enhanced the interaction between glycogen synthase kinase 3β (GSK3β) and TANK-binding kinase 1 (TBK1) to promote IFN-β production. Our findings revealed that EETs and sEH inhibitors prevent the progress of CVB3-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.