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BML‐111 treatment prevents cardiac apoptosis and oxidative stress in a mouse model of autoimmune myocarditis
Author(s) -
Jaén Rafael I.,
FernándezVelasco María,
Terrón Verónica,
SánchezGarcía Sergio,
Zaragoza Carlos,
CanalesBueno Natalia,
ValBlasco Almudena,
VallejoCremades María Teresa,
Boscá Lisardo,
Prieto Patricia
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000611r
Subject(s) - myocarditis , oxidative stress , inflammation , medicine , fibrosis , apoptosis , diabetic cardiomyopathy , immunology , cardiomyopathy , cancer research , pathology , biology , heart failure , biochemistry
Myocarditis is an inflammation of the myocardium that can progress to a more severe phenotype of dilated cardiomyopathy (DCM). Three main harmful factors determine this progression: inflammation, cell death, and oxidative stress. Lipoxins and their derivatives are endogenous proresolving mediators that induce the resolution of the inflammatory process. This study aims to determine whether these mediators play a protective role in a murine model of experimental autoimmune myocarditis (EAM) by treating with the lipoxin A 4 analog BML‐111. We observed that EAM mice presented extensive infiltration areas that correlated with higher levels of inflammatory and cardiac damage markers. Both parameters were significantly reduced in BML‐treated EAM mice. Consistently, cardiac dysfunction, hypertrophy, and emerging fibrosis detected in EAM mice was prevented by BML‐111 treatment. At the molecular level, we demonstrated that treatment with BML‐111 hampered apoptosis and oxidative stress induction by EAM. Moreover, both in vivo and in vitro studies revealed that these beneficial effects were mediated by activation of Nrf2 pathway through CaMKK2‐AMPKα kinase pathway. Altogether, our data indicate that treatment with the lipoxin derivative BML‐111 effectively alleviates EAM outcome and prevents cardiac dysfunction, thus, underscoring the therapeutic potential of lipoxins and their derivatives to treat myocarditis and other inflammatory cardiovascular diseases.