Specialized Pro-Resolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and Nrf2 Activation

Myocarditis is a severe inflammatory heart disease and a precursor of dilated cardiomyopathy. Despite progress in the understanding of the disease, there is currently no specific treatment available for myocarditis. Lipoxins and their derivatives promote the resolution of inflammation, and help recover tissue homeostasis; however, their role in cardiac inflammation is poorly understood. 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. Enhanced cardiac oxidative profile and reduced activation of NRF2, a master antioxidant transcription factor was revealed in EAM-induced mice. Administration of BML-111 to EAM-induced mice prevented all pathological changes, whereas co-administration of the NRF2 inhibitor luteolin to EAM-treated mice blunted the BML-111-induced activation of NRF2 and the accompanying protective effects on cardiac function and intracellular Ca2+ dynamics. 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 (SR Ca2+-ATPase), but failed to induce any functional change in cells from Nrf2-/- knockout mice. Mechanistically, BML-111 increased SERCA2a cardiac expression in wild-type mice, and regulation of the expression of NRF2 determined SERCA2a expression in human ventricular cells. Finally, human myocarditis-positive myocardium showed a reduced expression of both ATP2A2 and NFE2L2 coding genes for SERCA2a and NRF2, respectively. Our results highlight new cardioprotective mechanisms of pro-resolving lipid mediators, emerging as innovative treatments for myocarditis.