Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling

Zhou Zhou; Min Zhang; Chengcheng Zhao; Xu Gao; Zheng Wen; Junfang Wu; Chen Chen; Ingrid Fleming; Jiong Hu; Dao Wen Wang

doi:10.1161/CIRCRESAHA.123.322619

Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling

Circ Res. 2023 Oct 13;133(9):772-788. doi: 10.1161/CIRCRESAHA.123.322619. Epub 2023 Sep 8.

Authors

Zhou Zhou^{1

2}, Min Zhang^{1

2}, Chengcheng Zhao^{1

2}, Xu Gao^{1

2}, Zheng Wen^{1

2}, Junfang Wu^{1

2}, Chen Chen^{1

2}, Ingrid Fleming^{3

4

5}, Jiong Hu^{6

3

4

5}, Dao Wen Wang^{1

3

2}

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Tongji Hospital (Z.Z., M.Z., C.Z., X.G., Z.W., J.W., C.C., D.W.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China (Z.Z., M.Z., C.Z., X.G., Z.W., J.W., C.C., D.W.W.).
³ Sino-German Laboratory of CardioPulmonary Science (I.F., J.H., D.W.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany (I.F., J.H.).
⁵ German Center of Cardiovascular Research, Partner Site RheinMain, Frankfurt am Main, Germany (I.F., J.H.).
⁶ Department of Histology and Embryology, School of Basic Medicine (J.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

PMID: 37681352
DOI: 10.1161/CIRCRESAHA.123.322619

Abstract

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

Keywords: arachidonic acid; epoxide hydrolases; glycogen synthase kinase 3 beta; inflammation; interferon type I; myocarditis.