Cardiac-Specific Overexpression of Tumor Necrosis Factor-α Causes Oxidative Stress and Contractile Dysfunction in Mouse Diaphragm

Li, Xia; Moody, Melanie R.; Engel, David; Walker, Stacey; Clubb, Fred J.; Sivasubramanian, Natarajan; Mann, Douglas L.; Reid, Michael B.

doi:10.1161/01.cir.102.14.1690

Cited by 199 publications

(166 citation statements)

References 32 publications

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“…It is therefore reasonable to speculate that the enhanced diaphragm free radical generation observed in the present study may be cytokine induced. This possibility is supported by recent work by Li et al (15).…”

Section: Discussionsupporting

confidence: 67%

Diaphragmatic free radical generation increases in an animal model of heart failure

Supinski

Callahan²

2005

Journal of Applied Physiology

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Supinski, Gerald S., and Leigh A. Callahan. Diaphragmatic free radical generation increases in an animal model of heart failure. J Appl Physiol 99: 1078 -1084, 2005; doi:10.1152/japplphysiol.01145.2004.-Heart failure evokes diaphragm weakness, but the mechanism(s) by which this occurs are not known. We postulated that heart failure increases diaphragm free radical generation and that free radicals trigger diaphragm dysfunction in this condition. The purpose of the present study was to test this hypothesis. Experiments were performed using halothaneanesthetized sham-operated control rats and rats in which myocardial infarction was induced by ligation of the left anterior descending coronary artery. Animals were killed 6 wk after surgery, the diaphragms were removed, and the following were assessed: 1) mitochondrial hydrogen peroxide (H2O2) generation, 2) free radical generation in resting and contracting intact diaphragm using a fluorescent-indicator technique, 3) 8-isoprostane and protein carbonyls (indexes of free radical-induced lipid and protein oxidation), and 4) the diaphragm force-frequency relationship. In additional experiments, a group of coronary ligation animals were treated with polyethylene glycol-superoxide dismutase (PEG-SOD, 2,000 units⅐kg Ϫ1 ⅐day Ϫ1) for 4 wk. We found that coronary ligation evoked an increase in free radical formation by the intact diaphragm, increased diaphragm mitochondrial H2O2 generation, increased diaphragm protein carbonyl levels, and increased diaphragm 8-isoprostane levels compared with controls (P Ͻ 0.001 for the first 3 comparisons, P Ͻ 0.05 for 8-isoprostane levels). Force generated in response to 20-Hz stimulation was reduced by coronary ligation (P Ͻ 0.05); PEG-SOD administration restored force to control levels (P Ͻ 0.03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation. oxidative stress CONGESTIVE HEART FAILURE IS known to evoke significant changes in skeletal muscle function, inducing muscle wasting, reductions in muscle force-generating capacity, and alterations in muscle energy metabolism (9,16,20). Both limb and respiratory skeletal muscle are thought to be affected in this condition (28). Some work indicates that limb skeletal muscle dysfunction plays an important role in determining exercise capacity in patients with congestive heart failure (22). In addition, respiratory muscle dysfunction may predispose these patients to respiratory failure under conditions in which the respiratory workload increases (28).The mechanism by which congestive heart failure alters skeletal muscle function remains unclear. Importantly, evidence indicates that inactivity alone cannot fully account for congestive heart failure-induced reductions in muscle function (25). Recent work indicates, however, that congestive heart failure is associated with an increase in generation of free radicals (i.e., molecules derived from superoxide anions) an...

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Section: Discussionsupporting

confidence: 67%

Diaphragmatic free radical generation increases in an animal model of heart failure

Supinski

Callahan²

2005

Journal of Applied Physiology

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“…The study was performed on hemizygous MHCsTNF mice generated in an ICR ϫ C57 background (18,32) and on age-matched wild-type (WT) littermate controls. All mice (age 8 -16 wk) were anesthetized by intraperitoneal injection (15 ml/kg) of a mixture of pentobarbital sodium (4.1 mg/ml), sodium chloride (6.6 mg/ml), and ethanol (0.18 ml/ml).…”

Section: Animalsmentioning

confidence: 99%

Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor

Sawaya

Rajawat

Rami

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…11,12 For example, reactive oxygen species can activate reactive oxygen species-sensitive transcription factors such as nuclear factor-B and activator protein-1, which mediate the expression of ICAM-1, 44 leading to the recruitment of inflammatory cells and the elaboration of inflammatory cytokines such as tumor necrosis factor-␣. 45 Because both reactive oxygen species and inflammatory cytokines have been shown to mediate alterations in the interstitial matrix 46 and myocyte apoptosis, 47 it is possible that the beneficial effects of EPL are due, at least in part, to reductions in both oxidative stress and inflammation.…”

Section: Oxidative Stress and Inflammationmentioning

confidence: 99%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

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Cardiac-Specific Overexpression of Tumor Necrosis Factor-α Causes Oxidative Stress and Contractile Dysfunction in Mouse Diaphragm

Abstract: Elevated circulating levels of TNF-alpha provoke contractile dysfunction in the diaphragm through an endocrine mechanism thought to be mediated by oxidative stress.

Cited by 199 publications

References 32 publications

Diaphragmatic free radical generation increases in an animal model of heart failure

Diaphragmatic free radical generation increases in an animal model of heart failure

Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

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