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Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum–adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis., This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (SAF-2017-84777R), Instituto de Salud Carlos III (ISCIII) (PI17/01093, PI17/01344, and PI20/01482), Sociedad Española de Cardiología, Proyecto Traslacional 2019 and Asociación del Ritmo Cardiaco (SEC, España), Proyecto Asociación Insuficiencia Cardiaca (Trasplante Cardiaco) 2020, Fondo Europeo de Desarrollo Regional, Fondo Social Europeo, and CIBERCV, a network funded by ISCIII, Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 PID2020-113238RB-I00, PID2019-105600RB-I00, the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 [PT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed]), and “la Caixa” Foundation (project code HR17-00247). The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades. Dr Ruiz-Hurtado is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). Dr Tamayo and R.I. Jaén, and M. Gil-Fernández were or currently are PhD students funded by the Formación de Profesorado Universitario program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135; FPU16/00827, FPU1901973).

Background and purpose Myocarditis is a severe inflammatory heart disease and a leading cause of sudden death in young adults; but currently no specific treatment is available. Lipoxins and their derivatives promote the resolution of inflammation contributing to recover tissue homeostasis; but their role in cardiac inflammation is poorly understood. Methods and results BML-111, a stable lipoxin A4 receptor agonist, protects against cardiac dysfunction in a murine model of experimental autoimmune myocarditis (EAM) by preventing Ca2+ mishandling. Cardiac proteomic analysis revealed an enhanced cardiac oxidative profile in EAM-induced mice with reduced activation of NRF2, a master antioxidant transcription factor. In vitro analysis showed that 15-epi-lipoxin A4 increased systolic Ca2+ release and sarcoplasmic reticulum (SR)-Ca2+ load in cardiomyocytes isolated from wild-type mice and augmented the rate of SR-Ca2+ uptake by SERCA2a, but failed to induce any functional change in cells from Nrf2−/− mice. BML-111 increased SERCA2a cardiac expression in wild-type mice, and the transcriptional activity of Nrf2 determined SERCA2a expression in human ventricular cells. Human myocarditis-positive myocardium showed a reduced expression of both ATP2A2 (SERCA2a) and NF2L2 (NRF2). Conclusions Our results demonstrated new cardioprotective mechanisms of pro-resolving lipid mediators that may emerge as innovative treatments for myocarditis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII [PI17/01344]), Sociedad Española de Cardiología: Proyecto Traslacional 2019Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca

Trabajo presentado en el ESC Congress 2021 - The Digital Experience, celebrado en modalidad virtual el 27 de agosto de 2021.