In vivo TNF-α inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure

Abstract

Heart failure is associated with increased myocardial expression of TNF-alpha. However, the role of TNF-alpha in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF-alpha to myocardial mitochondrial dysfunction, oxidative stress, and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathological processes. Male mongrel dogs were randomly assigned (n = 10 each) to 1) normal controls; 2) chronic pacing (250 beats/min for 4 wk) 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 with 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 TUNEL-positive 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-alpha 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.

TNF Receptor 1/2 Predict Heart Failure Risk in Type 2 Diabetes Mellitus Patients

“…[5][6][7][8] Tumor necrosis factor (TNF) in particular is well known to have harmful effects on cardiomyocyte contractility in HF by inducing reactive oxygen species formation, cardiomyocyte hypertrophy, and apoptosis. 9,10) Diabetes mellitus (DM), is an independent risk factor of coronary artery disease in terms of serious long-term complications. DM has also been shown to be affected by multi-inflammatory factors such as toll like receptors, interleukin, TNF, and other cytokine factors.…”

TNF-α dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation

“…In cardiac and endothelial cells, signaling mechanisms for TNF-␣ involve mitochondria (20, 23-25, 35, 36). TNF-␣ disrupted the mitochondrial electron transport chain, caused release of cytochrome c, induced mitochondrial ROS generation, and triggered apoptosis (14,28,30,41,52). Although the downstream intramitochondrial target for TNF-␣ is unclear, PTP involvement was proposed in endothelial cells (52).…”

“…TNF-␣-induced intracellular signaling may involve mitochondrial PTP activation and ceramide generation (14,22,28,30,39,41,52). However, ceramide did not alter transient K Ca currents, indicating that it is unlikely to mediate TNF-␣-induced activation of these events (Fig.…”

Inflammatory cell tumor necrosis factor signaling modulates post-infarction left ventricular remodeling.

“…First, elevated plasma levels of TNF and IL-6, as well as soluble TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) function as independent predictors of mortality in HF patients [31,39,40]. Secondly, in experimental animal models, TNF via infusion or over expression, can reproduce many of the phenotypic responses noted in HF, specifically depressed contractile function [41][42][43], myocyte hypertrophy [28,44], P-AR uncoupling [43], apoptosis [45], and ROS production [46] indicating that TNF in sufficient levels, even in the absence of antecedent injury, can decrease myocardial performance. Third, mice with cardiac-specific TNF over-expression suffer a premature death with a dilated cardiomyopathy, characterized by many of the same pathologic findings seen in chronic ischemic HF [47][48][49].…”

“…Secondly, in experimental animal models, TNF infusion or over-expression reproduces many of the phenotypic responses noted in HF [28,[41][42][43][44][45][46]. Also, TNF has been shown to be a foundation cytokine in that has the ability to modify the expression of the other pro-inflammatory cytokines such as IL-113 and IL-6 [50,51].…”