title: Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice.
abstract: The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative/oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS(+/+)) and inducible nitric oxide synthase-deficient (iNOS(-/-)) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS(+/+) mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS(-/-) mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS(-/-) mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis.
authors: Instituto de Biotecnología, Departamento de Fisiología, Universidad de Granada, Spain.
authors: Germaine
authors: G
authors: Escames
authors: Luis C
authors: LC
authors: López
authors: Francisco
authors: F
authors: Ortiz
authors: Ana
authors: A
authors: López
authors: José A
authors: JA
authors: García
authors: Eduardo
authors: E
authors: Ros
authors: Darío
authors: D
authors: Acuña-Castroviejo
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004579:Electron Transport; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
chemical_list: D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; D000251:Adenosine Triphosphatases; D008550:Melatonin