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: Francisco Ortiz, José A García, Darío Acuña-Castroviejo, Carolina Doerrier, Ana López, Carmen Venegas, Huayqui Volt, Marta Luna-Sánchez, Luis C López, Germaine Escames
• Journal: Journal of pineal research (J Pineal Res) Vol. 56 Issue 1 Pg. 71-81 (Jan 2014) ISSN: 1600-079X [Electronic] England
• PMID: 24117944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Antioxidants
• Mitochondrial Proteins
• Nitric Oxide
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nos1 protein, mouse
• Nos2 protein, mouse
• Glutathione
• Melatonin

Topics

• Analysis of Variance
• Animals
• Antioxidants (pharmacology)
• Cytosol (chemistry, drug effects, metabolism)
• Disease Models, Animal
• Glutathione (analysis, metabolism)
• Lipid Peroxidation (drug effects)
• Melatonin (pharmacology)
• Mice
• Mice, Knockout
• Mitochondria (chemistry, drug effects, metabolism)
• Mitochondrial Proteins (analysis, metabolism)
• Myocardium (cytology)
• Nitric Oxide
• Nitric Oxide Synthase Type I (analysis, genetics, metabolism)
• Nitric Oxide Synthase Type II (analysis, genetics, metabolism)
• Oxidative Stress (drug effects)
• Sepsis (metabolism)