Tumor necrosis factor-α-induced caspase activation mediates endotoxin-related cardiac dysfunction*

Carlson, Deborah; Willis, Monte S.; White, D. Jean; Horton, Jureta W.; Giroir, Brett P.

doi:10.1097/01.ccm.0000163398.79679.66

Cited by 106 publications

(76 citation statements)

References 64 publications

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“…It should be emphasized that proteases function in IB␣ degradation, as previously established (6). Calpain inhibitor III and PD-150606 are relatively specific inhibitors of calpain.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice

Luo

Chen

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Recent studies in septic models have shown that myocardial calpain activity and TNF-␣ expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-␣ expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IB␣/NF-B signaling linked myocardial calpain activity and TNF-␣ expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IB␣/NF-B signaling activity, and TNF-␣ expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-␣ expression were increased and IB␣ protein was degraded. Furthermore, NF-B was activated, as indicated by increased NF-B p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor and PD-150606 prevented the LPS-induced degradation of myocardial IB␣, NF-B activation, and TNF-␣ expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IB␣ protein degradation, and NF-B activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-B activation, TNF-␣ expression, and myocardial dysfunction in septic mice through IB␣ protein cleavage. sepsis; calpain; tumor necrosis factor-␣; IB␣/nuclear factor-B; myocardial dysfunction APPROXIMATELY 700,000 cases of sepsis occur each year in the United States, and this condition has an overall mortality rate of ϳ30% (1). Myocardial dysfunction is an early and fatal manifestation of sepsis in humans and animals (21,25,26), but the physiological basis of this effect and the molecular mediators that trigger myocardial dysfunction are not yet fully understood.Calpains are a family of Ca 2ϩ

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“…It should be emphasized that proteases function in IB␣ degradation, as previously established (6). Calpain inhibitor III and PD-150606 are relatively specific inhibitors of calpain.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice

Luo

Chen

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…We have previously shown that GP administration significantly blunted NF-B activation both in septic mice (43) and in ischemic hearts (28). NF-B is a critical transcription factor in TLR-mediated signaling pathways and plays a critical role in regulation of the expression of a number of genes, including inflammatory cytokines such as TNF-␣ and IL-1-␤, which have been shown to suppress cardiac function synergistically during sepsis (10). Unfortunately, anti-TNF-␣ or anti-IL-1-␤ therapy did not result in increased survival in patients with septic shock (12).…”

Section: Discussionmentioning

confidence: 99%

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Ha¹,

Fang²,

Grant³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice. Am J Physiol Heart Circ Physiol 291: H1910 -H1918, 2006. First published June 9, 2006 doi:10.1152/ajpheart.01264.2005.-Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLPinduced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (P Ͻ 0.05) and cardiomyocyte apoptosis by 7.8-fold (P Ͻ 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% (P Ͻ 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3␤, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.

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“…Carlson et al examined TNF-α-dependent apoptotic pathways in isolated mouse cardiomyocytes that worked via activation of specific proteases termed capsases [37]. They found LPS injection increased capsase-3 activity in cardiomyocytes, in association with pro-apoptotic patterns of gene expression and depressed left ventricular developed pressure in ex vivo hearts.…”

Section: Other Cytokine Effectsmentioning

confidence: 99%

Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms

2010

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Tumor necrosis factor-α-induced caspase activation mediates endotoxin-related cardiac dysfunction*

Abstract: Endotoxin induces a TNF-alpha-dependent apoptotic cascade in the myocardium, which contributes to the development of cardiac dysfunction.

Cited by 106 publications

References 64 publications

Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice

Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms

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