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Low Level Tumor Necrosis Factor-Alpha Protects Cardiomyocytes Against High Level Tumor Necrosis Factor-Alpha: Brief Insight into a Beneficial Paradox

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Abstract

Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by “low TNFα” helped cardiomyocyte to withstand toxicity from “high TNFα” or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNFα.

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Authors and Affiliations

  1. Internal Medicine Unit and Rheumatology Outpatients Clinic, “Ninetto Melli” Hospital, 72027, San Pietro V.co, Brindisi, Italy

    Fabio Cacciapaglia

  2. CIR and Drug Sciences, University Campus Bio-Medico, 00128, Rome, Italy

    Emanuela Salvatorelli, Giorgio Minotti & Pierantonio Menna

  3. Department of Clinical Medicine and Rheumatology, University Campus Bio-Medico of Rome, 00128, Rome, Italy

    Antonella Afeltra

Authors
  1. Fabio Cacciapaglia
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  2. Emanuela Salvatorelli
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  3. Giorgio Minotti
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  4. Antonella Afeltra
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  5. Pierantonio Menna
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Correspondence to Fabio Cacciapaglia.

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Cacciapaglia, F., Salvatorelli, E., Minotti, G. et al. Low Level Tumor Necrosis Factor-Alpha Protects Cardiomyocytes Against High Level Tumor Necrosis Factor-Alpha: Brief Insight into a Beneficial Paradox. Cardiovasc Toxicol 14, 387–392 (2014). https://doi.org/10.1007/s12012-014-9257-z

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  • DOI: https://doi.org/10.1007/s12012-014-9257-z

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