Overexpression of tumor necrosis factor-α activates both anti- and pro-apoptotic pathways in the myocardium

Kubota, Takeshi; Miyagishima, Masayuki; Kadokami, Toshiaki; Bounoutas, George S.; McTiernan, Charles F.; Feldman, Arthur M.

doi:10.1016/s1071-9164(99)91164-8

Cited by 50 publications

(76 citation statements)

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“…The concentration of TNF-␣ used in this study (10 ng/mL) was consistent with the range previously used on cardiac myocytes in vitro. 9 On the basis of these results, we concluded that TNF-␣ could damage mtDNA and cause mitochondrial dysfunction in cardiac myocytes via the increase of intracellular oxidative stress. These results add to a growing literature suggesting that ROS can act as signaling mediators of TNF-␣.…”

Section: Discussionmentioning

confidence: 86%

“…To determine the induction of apoptosis, cardiac myocytes were stained with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. 9 Staining with hematoxylin was carried out on the same section for visualization of nuclei. We also examined whether apoptosis is present in myocytes by the more sensitive ligationmediated polymerase chain reaction (PCR) fragmentation assay (ApoAlert LM-PCR ladder assay kit).…”

Section: Evaluation Of Myocyte Viabilitymentioning

confidence: 99%

“…We also examined whether apoptosis is present in myocytes by the more sensitive ligationmediated polymerase chain reaction (PCR) fragmentation assay (ApoAlert LM-PCR ladder assay kit). 9 …”

Section: Evaluation Of Myocyte Viabilitymentioning

confidence: 99%

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Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes

et al. 2003

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Background-Tumor necrosis factor-␣ (TNF-␣) and angiotensin II (Ang II) are implicated in the development and further progression of heart failure, which might be, at least in part, mediated by the production of reactive oxygen species (ROS). However, the cause and consequences of this agonist-mediated ROS production in cardiac myocytes have not been well defined. Recently, we demonstrated that increased ROS production was associated with mitochondrial DNA (mtDNA) damage and dysfunction in failing hearts. We thus investigated whether the direct exposure of cardiac myocytes to TNF-␣ and Ang II in vitro could induce mtDNA damage via production of ROS. Methods and Results-TNF-␣ increased ROS production within cultured neonatal rat ventricular myocytes after 1 hour, as assessed by 2Ј,7Ј-dichlorofluorescin diacetate fluorescence microscopy. TNF-␣ also decreased mtDNA copy number by Southern blot analysis in association with complex III activity, which was prevented in the presence of the antioxidant ␣-tocopherol. A direct exposure of myocytes to H 2 O 2 caused a similar decrease in mtDNA copy number. In contrast, Ang II did not affect mtDNA copy number, despite the similar increase in ROS production. TNF-␣-mediated ROS production and a decrease in mtDNA copy number were inhibited by the sphingomyelinase inhibitor D609. Furthermore, N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analogue, increased myocyte ROS production, suggesting that TNF-␣-mediated ROS production and subsequent mtDNA damage were mediated by the sphingomyelin-ceramide signaling pathway. Conclusions-The intimate link between TNF-␣, ROS, and mtDNA damage might play an important role in myocardial remodeling and failure.

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Section: Discussionmentioning

confidence: 86%

Section: Evaluation Of Myocyte Viabilitymentioning

confidence: 99%

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Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes

et al. 2003

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“…Taken together, these results indicate that TNF-a produced by cardiomyocytes may not serve as a direct trigger of cardiomyocyte apoptosis in vivo. 13,14,19 It has been shown recently that TNF-a activates dual signaling cascades, with one pathway leading to apoptosis, whereas another pathway, mediated through NF-kB, suppresses apoptosis. 45 Therefore, the latter signal pathway capable of preventing the development of cardiomyocyte apoptosis may play an important role in TNF-a signaling in the infarcted myocardium in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…17 However, there have been few studies on the expression pattern of TNF-a associated with cardiomyocyte apoptosis in human MI. 18,19 Therefore, the present study has examined the in vivo role of TNF-a in promoting apoptosis in cardiomyocytes by quantitative analysis of the distribution of TNF-a expression and ss-DNA-positive apoptosis in cardiomyocytes in human MI.…”

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confidence: 99%

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

et al. 2006

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To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-a, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (Po0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-a was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-a index in cardiomyocytes (r ¼ 0.08, P ¼ 0.37), suggesting that TNF-a does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-a produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.

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Ghrelin and toxicity: recent findings and future challenges

Vasileiou

Patsouras

Patsouris

et al. 2012

J of Applied Toxicology

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Ghrelin is a novel brain-gut peptide that plays various roles in mammals, including control of food intake and growth hormone release, as well as gastric motility and acid secretion in the gastrointestinal tract. It is mainly secreted by the gastric mucosa, but is also expressed in various other tissues. Different studies confirm the multiple biological roles of and possible protective effects of ghrelin. Multiple in vitro and in vivo studies support the powerful protective action of ghrelin against heart, gastric and liver injury. Moreover, ghrelin has been reported to be beneficial in renal tissue injury and excretory function after ischemia-reperfusion and to exert neuroprotective effects in cerebral ischemic regions. The aim of this review is to summarize and evaluate all the currently available in vivo and in vitro studies regarding the effects of ghrelin on tissue injury induced in different organs and tissues.

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Overexpression of tumor necrosis factor-α activates both anti- and pro-apoptotic pathways in the myocardium

Cited by 50 publications

References 0 publications

Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes

Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction

Ghrelin and toxicity: recent findings and future challenges

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