Protective effect of lipoxin A4 analog BML-111 on a murine model of autoimmune myocarditis

Abstract

Myocarditis is a cardiovascular disease characterized by a chronic inflammation of the myocardium that causes cardiac dysfunction. In the majority of patients this disease leads to dilated cardiomyopathy and represents the major cause of sudden cardiac death in young adults. Although it is a clinically severe disease, current treatments are inefficient and unspecific. In search for new therapies, lipoxins and their derivatives arise as a more effective and safer alternative thanks to their pro-resolving properties. The present work aimed to evaluate the effect of BML-111, a lipoxin A4 synthetic analog, in a murine model of autoimmune myocarditis (EAM) through molecular, histological and echocardiographic studies. We discovered that BML-111 treatment significantly improved cardiac function and reduced cardiac hypertrophy of myocarditisinduced mice. Furthermore, BML-111 also diminished infiltration of inflammatory cells in the heart and prevented the fibrotic process associated to cardiac remodeling. Lastly, we also observed that the levels of pro-inflammatory and pro-fibrotic molecular mediators (TGFβ, IL-6, TNFα and Galectin-3) in the heart decreased upon treatment. Together, these results demonstrate that BML-111 mitigates cardiac alterations associated to myocarditis by restoring cardiac function and reducing adverse cardiac remodeling. These findings highlight the therapeutic potential of lipoxins to treat myocarditis and provide new insights on the development of future therapies to alleviate the outcome of inflammatory heart diseases.