Honokiol attenuates oxidative stress-dependent heart dysfunction in chronic Chagas disease by targeting AMPK / NFE2L2 / SIRT3 signaling pathway

Abstract

Chronic cardiomyopathyis the most serious and frequent manifestation of Chagas disease caused by Trypanosoma cruzi. Free radicals are acrucial factor in Chagas pathogenesis. Parasite infection of cardiomyocytesexacerbates the release of mitochondrial reactive oxygen species (ROS), deeplyinvolved in remodeling and functional impairment of the heart. An insufficientantioxidant response further contributes to progression of cardiac oxidativedamage. We herein aimed to evaluatethe therapeutic potential of honokiol (HKL), a lignanconstituent of Magnolia species, to lower ROS generation and mitochondrial dysfunctionin chronic T. cruzi-elicitedcardiomyopathy. In vitro experimentsrevealed that HKL decreases ROS levels in infected murine atrial cells via theAMPK / NFE2L2 / SIRT3 axis. Likewise, HKL administration to Chagasic micetargeted this myocardial signaling pathway leading to deacetylation andactivation of mitochondrial antioxidant enzymes, thereby enabling effectivecontrol of ROS production and adduct formation. Concomitantly, HKL therapyattenuated echocardiographic alterations, leukocyte infiltration and collagendeposition in cardiac tissue from mice upon 130 days of infection. Overall,these data show that SIRT3 targeting by HKL is a potential therapeutic strategyto prevent the long-term evolution of T.cruzi-driven cardiomyopathy, which may be helpful in averting oxidativestress-induced mitochondrial deficiencies and the decay of antioxidantdefenses. Our findings open up a valuable new avenue for the challengingtreatment of chronic Chagas heart disease.