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inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress and apoptosis in experimental heart failure
1 Terrence Donnelly Heart Program, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
2 The Molecular Cardiology Institute, Highland Park, New Jersey, USA
3 Department of Medicine, Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: moeg{at}smh.toronto.on.ca.
Heart failure is associated with increased myocardial expression of tumor necrosis factor-
(TNF-). However, the role of TNF- in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF- to myocardial mitochondrial dysfunction, oxidative stress and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathologic processes. Male Mongrel dogs were
randomly assigned (n=10 each) to: 1) normal controls, 2) chronic pacing (250 beats/min for 4 weeks) with concomitant administration of etanercept, a soluble p75 TNF receptor fusion protein, 0.5 mg/kg subcutaneously twice weekly, 3) chronic pacing with administration of saline vehicle. Mitochondrial function was assessed by left ventricular (LV) tissue mitochondrial respiratory enzyme activities. Oxidative stress was assessed by aldehyde levels and apoptosis was quantified by photometric enzyme immunoassay for cytoplasmic histone-associated DNA fragments and terminal deoxynucleotide transferase-mediated nick-end labeling (TUNEL) assays. LV activity levels of mitochondrial respiratory chain enzyme complex III and V were reduced in the saline-treated dogs, and restored either partially (complex III) or completely (complex V) in the etanercept-treated dogs. Aldehyde levels, DNA fragments and TUNELpositive cells were increased in the saline-treated dogs and normalized in etanercept-treated
dogs. These changes were accompanied by an attenuation of LV dilatation and partial restoration of ejection fraction. Our data demonstrate that TNF- contributes to progressive LV dysfunction in pacing-induced heart failure, mediated in part by a local impairment in mitochondrial function and increase in oxidative stress and myocyte apoptosis.
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