Specialized pro-resolving mediators prevents cardiac dysfunction by modulating Ca2+ handling and NRF2 axis

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