Melatonin alleviates sepsis-induced heart injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammaso
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ORIGINAL ARTICLE
Melatonin alleviates sepsis-induced heart injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammasome Ibtissem Rahim 1,2,3 & Ramy K. Sayed 1,4 & Marisol Fernández-Ortiz 1 & Paula Aranda-Martínez 1 & Ana Guerra-Librero 1 & José Fernández-Martínez 1 & Iryna Rusanova 1 & Germaine Escames 1,5 & Bahia Djerdjouri 3 & Darío Acuña-Castroviejo 1,5 Received: 23 April 2020 / Accepted: 31 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Melatonin improved the outcome of septic cardiomyopathy by inhibiting NLRP3 priming induced by reactive oxygen species. To get insights into these events, we studied the melatonin/Nrf2 antioxidant pathways during sepsis in the heart of NLRP3deficient mice. Sepsis was induced by cecal ligation and puncture and melatonin was given at a dose of 30 mg/kg. Nuclear turnover of Nrf2 and p-Ser40 Nrf2 and expression of ho-1 were enhanced in nlrp3+/+ and nlrp3−/− mice during sepsis. Sepsis caused higher mitochondria impairment, apoptotic and autophagic events in nlrp3+/+ mice than in nlrp3−/− animals. These findings were accompanied by greater levels of Parkin and PINK-1, and lower Mfn2/Drp-1 ratio in nlrp3+/+ than in nlrp3−/− mice during sepsis, supporting less mitophagy in the latter. Ultrastructural analysis of myocardial tissue further confirmed these observations. The activation of NLRP3 inflammasome accounted for most of the deleterious effects of sepsis, whereas the Nrf2dependent antioxidative response activation in response to sepsis was unable to neutralize these events. In turn, melatonin further enhanced the Nrf2 response in both mice strains and reduced the NLRP3 inflammasome activation in nlrp3+/+ mice, restoring myocardial homeostasis. The data support that the anti-inflammatory efficacy of melatonin against sepsis depends, at least in part, on Nrf2 activation. Keywords NLRP3 deficiency . Nrf2 . Sepsis . Melatonin . Apoptosis . Mitochondria
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01972-5) contains supplementary material, which is available to authorized users. * Darío Acuña-Castroviejo [email protected] 1
Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, 18016 Granada, Spain
2
Département de Biologie et Physiologie Cellulaire, Faculté des Sciences de la Nature et de la Vie, Université Blida 1, 09000 Blida, Algeria
3
Faculté des Sciences Biologiques, Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene, Bab-Ezzouar, 16111 Algiers, Algeria
4
Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt
5
CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, 18016 Granada, Spain
Septic cardiomyopathy is a common cause of death in intensive care units (Hunter and Doddi 2
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