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Cardiovascular Research 2000 45(3):595-602; doi:10.1016/S0008-6363(99)00395-8
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Tumor necrosis factor-{alpha} induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes

Wei Song, Xiangru Lu and Qingping Feng*

Cardiology Research Laboratory, London Health Sciences Centre, Department of Medicine, Cardiology Division, Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, N6A 4G5 Canada

* Corresponding author. Tel.: +1-519-685-8300, ext. 75502; fax +1-519-432-7367 qfeng{at}julian.uwo.ca

Objective: It has been demonstrated that tumor necrosis factor-{alpha} (TNF{alpha}) induces apoptosis in cardiac myocytes. However, its mechanism of action is still not well understood. In the present study, we hypothesized that TNF{alpha} induces myocardial apoptosis by induction of inducible nitric oxide synthase (iNOS). Methods: Neonatal cardiac myocytes were isolated from iNOS (–/–) mutant and C57BL6 wild type mice. Cells were cultured for 3 days before treatment with an NO donor or TNF{alpha}. Following treatment with S-nitroso-N-acetyl-penicillamine (SNAP) or TNF-{alpha}, cells were tested for apoptosis by terminal deoxynucleotidyl transfer-mediated end labeling (TUNEL) staining and cell death detection ELISA. NO production was measured by nitrite concentration in the culture medium. Cardiomyocyte expression of iNOS and TNF type 1 receptor (TNFR1) mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Results: SNAP (0.01–100 µM) induced apoptosis of cardiac myocytes in a concentration-dependent manner in the wild type mice (n=5, P<0.01). TNFR1 mRNA was expressed in neonatal cardiomyocytes from both wild type and iNOS (–/–) mutant mice. TNF{alpha} induced a concentration-dependent increase in iNOS mRNA expression and nitrite production as well as significant apoptosis of cardiomyocytes in the wild type mice (n=4, P<0.01). However, without iNOS expression, the apoptotic effects of TNF-{alpha} were significantly attenuated in cardiomyocytes from iNOS (–/–) mutant mice (n=4, P<0.05). Conclusion: TNF{alpha} induces apoptosis via iNOS expression and NO production in neonatal mouse cardiomyocytes.

KEYWORDS Apoptosis; Myocytes; Nitric oxide


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