title: The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS.
abstract: While it is accepted that the high production of nitric oxide (NO˙) by the inducible nitric oxide synthase (iNOS) impairs cardiac mitochondrial function during sepsis, the role of neuronal nitric oxide synthase (nNOS) may be protective. During sepsis, there is a significantly increase in the expression and activity of mitochondrial iNOS (i-mtNOS), which parallels the changes in cytosolic iNOS. The existence of a constitutive NOS form (c-mtNOS) in heart mitochondria has been also described, but its role in the heart failure during sepsis remains unclear. Herein, we analyzed the changes in mitochondrial oxidative stress and bioenergetics in wild-type and nNOS-deficient mice during sepsis, and the role of melatonin, a known antioxidant, in these changes. Sepsis was induced by cecal ligation and puncture, and heart mitochondria were analyzed for NOS expression and activity, nitrites, lipid peroxidation, glutathione and glutathione redox enzymes, oxidized proteins, and respiratory chain activity in vehicle- and melatonin-treated mice. Our data show that sepsis produced a similar induction of iNOS/i-mtNOS and comparable inhibition of the respiratory chain activity in wild-type and in nNOS-deficient mice. Sepsis also increased mitochondrial oxidative/nitrosative stress to a similar extent in both mice strains. Melatonin administration inhibited iNOS/i-mtNOS induction, restored mitochondrial homeostasis in septic mice, and preserved the activity of nNOS/c-mtNOS. The effects of melatonin were unrelated to the presence or the absence of nNOS. Our observations show a lack of effect of nNOS on heart bioenergetic impairment during sepsis and further support the beneficial actions of melatonin in sepsis.
authors.affiliation: Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Instituto de Biotecnología, Universidad de Granada, Granada, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortiz
authors.forename: José A
authors.initials: JA
authors.lastname: García
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
authors.forename: Carolina
authors.initials: C
authors.lastname: Doerrier
authors.forename: Ana
authors.initials: A
authors.lastname: López
authors.forename: Carmen
authors.initials: C
authors.lastname: Venegas
authors.forename: Huayqui
authors.initials: H
authors.lastname: Volt
authors.forename: Marta
authors.initials: M
authors.lastname: Luna-Sánchez
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D018805:Sepsis / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D024101:Mitochondrial Proteins; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D005978:Glutathione; D008550:Melatonin
keywords: antioxidant; free radicals; heart; melatonin; mitochondria; nitric oxide; nitric oxide synthases