Therapeutic role of lipoxins in cardiovascular disease: Mechanisms of lipoxin-mediated cardioprotection in myocarditis and dilated cardiomyopathy

Abstract

Inflammation is a defensive response of the organism upon a potential damaging agent with the main purpose of restoring tissue homeostasis. Numerous studies have demonstrated that dysregulation of this process underpins multiple prevalent pathologies including arthritis, cancer or cardiovascular diseases (CVDs). Once the danger signal is eliminated, a resolutive process ensues inflammation aiming to promote tissue repair by modulating several protective responses. With this purpose, a series of specific mediators known as specialized pro-resolving mediators (SPMs), are endogenously produced during resolution. Among SPMs, lipoxins (LXs) have been extensively proven to exert beneficial effects in different animal models of asthma, arthritis and periodontitis, with preliminary results in clinical trials. Nonetheless, their role in other pathologies like CVDs, which represent the main global cause of mortality and morbidity in the present, is still under research. In this work, our main objective is to evaluate the cardioprotective potential of LXs in the context of myocarditis and its progression to dilated cardiomyopathy (DCM), which are CVDs characterized by a profound inflammatory background. In the first place, we developed an animal model of experimental autoimmune myocarditis (EAM) that reliable reproduces human myocarditis in mice, and treated these with BML-111, a LX analog with enhanced efficacy and stability in vivo. Thus, we demonstrated that BML-treated EAM mice exhibited reduced immune cell infiltration and diminished levels of pro-inflammatory mediators in the heart in contrast to vehicle-treated EAM animals. In addition, we determined that this SPM managed to reduce significantly cardiac dysfunction observed in EAM mice by echocardiography. BML-111 administration leads to this improvement on cardiac function by modulating different responses at into the heart. First, BML-111 treatment decreased cardiomyocyte apoptosis and consequently, attenuated maladaptive hypertrophy and fibrosis in EAM mice. Furthermore, we observed that cardiomyocytes from EAM group presented defective cell contractility associated with Ca2+ mishandling, which was restored with BML-111. Analysis of molecular signaling revealed that BML-111 treatment protected from cardiac alterations by blunting cardiac oxidative stress in EAM mice, which was mainly mediated by the activation of the NRF2 antioxidant response via CaMKK2/AMPKα. In the last part of this work, we focused on a translational approach and analyzed LXA4 levels in sera from DCM patients. In accordance with our animal model, we observed that LXA4 levels negatively correlated with cardiac damage and inflammation markers in DCM patients. Altogether, in this work we deciphered novel pro-resolutive pathways modulated by LXs in CVD, providing new insights for the future evaluation of the cardioprotective potential of LXs in translational and clinical research. In conclusion, these data suggest that LXs may represent new promising therapeutic targets for the design of treatments toward CVDs with an inflammatory background