Tài liệu Báo cáo khoa học: Attenuation of cardiac mitochondrial dysfunction by melatonin in septic

Attenuation of cardiac mitochondrial dysfunction

by melatonin in septic mice

Germaine Escames1

, Luis C. Lo´ pez1

, Francisco Ortiz1

, Ana Lo´ pez1

, Jose´ A. Garcı´a1

, Eduardo Ros2

and Darı´o Acun˜ a-Castroviejo1,3

1 Instituto de Biotecnologı´a, Departamento de Fisiologı´a, Universidad de Granada, Spain

2 Servicio de Angiologı´a y Cirugı´a Vascular, Hospital Universitario San Cecilio, Granada, Spain

3 Servicio de Ana´lisis Clı´nicos, Hospital Universitario San Cecilio, Granada, Spain

Sepsis-induced multiple organ failure is the major

cause of mortality in critically ill patients, and its inci￾dence is rising [1]. The heart and cardiovascular sys￾tems are seriously affected during sepsis [2]. Although

myocardial impairment in sepsis has been extensively

studied, its etiology remains unclear [3]. Some reports

Keywords

ATP production; mitochondrial failure;

mitochondrial nitric oxide synthase;

oxidative stress; therapy

Correspondence

D. Acun˜ a-Castroviejo, Departamento de

Fisiologı´a, Facultad de Medicina, Avenida de

Madrid 11, E-18012, Spain

Fax: +34 958246295

Tel: +34 958246631

E-mail: [email protected]

(Received 4 December 2006, revised 9

February 2007, accepted 23 February 2007)

doi:10.1111/j.1742-4658.2007.05755.x

The existence of an inducible mitochondrial nitric oxide synthase has been

recently related to the nitrosative ⁄ oxidative damage and mitochondrial dys￾function 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 ⁄ indu￾cible mitochondrial nitric oxide synthase expression and activity, bioener￾getics 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 melato￾nin 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 mito￾chondrial nitric oxide synthase in iNOS+ ⁄ + mice that was accompanied by

oxidative stress, respiratory chain impairment, and reduced ATP produc￾tion, 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 syn￾thase activity, as both inducible nitric oxide synthase and inducible mito￾chondrial nitric oxide synthase were absent in iNOS– ⁄ – mice. The induction

of inducible mitochondrial nitric oxide synthase was associated with mito￾chondrial dysfunction, because heart mitochondria from iNOS– ⁄ – mice

were unaffected during sepsis. Melatonin treatment blunted sepsis-induced

inducible nitric oxide synthase ⁄ inducible mitochondrial nitric oxide syn￾thase isoforms, prevented the impairment of mitochondrial homeostasis

under sepsis, and restored ATP production. These properties of melatonin

should be considered in clinical sepsis.

Abbreviations

CLP, cecal ligation and puncture; ETC, electron transport chain; GPx, glutathione peroxidase; GRd, glutathione reductase; GSH, glutathione;

GSSG, oxidized glutathione; iNOS, inducible nitric oxide synthase; i-mtNOS, inducible mitochondrial nitric oxide synthase; LPO, lipid

peroxidation; mtNOS, constitutive mitochondrial nitric oxide synthase; nNOS, neuronal nitric oxide synthase.

FEBS Journal 274 (2007) 2135–2147 ª 2007 The Authors Journal compilation ª 2007 FEBS 2135