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Cardiovasc Res. 2014 Jul 1;103(1):90-9. doi: 10.1093/cvr/cvu112. Epub 2014 May 6.

TNF-α-mediated caspase-8 activation induces ROS production and TRPM2 activation in adult ventricular myocytes.

Author information

1
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France.
2
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Department of Medicine, Karolinska Institutet, Stockholm, Sweden Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
3
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
4
Department of Physical Therapy, School of Health Sciences, Ariel University, Ariel, Israel.
5
INSERM U1046, Université Montpellier 1, Université Montpellier 2, Montpellier, France jeremy.fauconnier@inserm.fr.

Abstract

AIMS:

TRPM2 is a Ca(2+)-permeable cationic channel of the transient receptor potential (TRP) superfamily that is linked to apoptotic signalling. Its involvement in cardiac pathophysiology is unknown. The aim of this study was to determine whether the pro-apoptotic cytokine tumour necrosis factor-α (TNF-α) induces a TRPM2-like current in murine ventricular cardiomyocytes.

METHODS AND RESULTS:

Adult isolated cardiomyocytes from C57BL/6 mice were exposed to TNF-α (10 ng/mL). Western blotting showed TRPM2 expression, which was not changed after TNF-α incubation. Using patch clamp in whole-cell configuration, a non-specific cation current was recorded after exposure to TNF-α (ITNF), which reached maximal steady-state amplitude after 3 h incubation. ITNF was inhibited by the caspase-8 inhibitor z-IETD-fmk, the antioxidant N-acetylcysteine, and the TRPM2 inhibitors clotrimazole, N-(P-amylcinnamoyl) anthranilic acid and flufenamic acid (FFA). TRPM2 has previously been shown to be activated by ADP-ribose, which is produced by poly(ADP-ribose) polymerase 1 (PARP-1). TNF-α exposure resulted in increased poly-ADP-ribosylation of proteins and the PARP-1 inhibitor 3-aminobenzamide inhibited ITNF. TNF-α exposure increased the mitochondrial production of reactive oxygen species (ROS; measured with the fluorescent indicator MitoSOX Red), and this increase was blocked by the caspase-8 inhibitor z-IETD-fmk. Clotrimazole and TRPM2 inhibitory antibody decreased TNF-α-induced cardiomyocyte death.

CONCLUSION:

These results demonstrate that TNF-α induces a TRPM2 current in adult ventricular cardiomyocytes. TNF-α induces caspase-8 activation leading to ROS production, PARP-1 activation, and ADP-ribose production. TNF-induced TRPM2 activation may contribute to cardiomyocyte cell death.

KEYWORDS:

Cardiac; Cell death; Ischaemia–reperfusion; TNF-α; TRPM2

PMID:
24802330
DOI:
10.1093/cvr/cvu112
[Indexed for MEDLINE]
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