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Cardiovascular Research 2004 62(3):558-567; doi:10.1016/j.cardiores.2004.01.039
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species–TNF{alpha}–caspase signaling pathway

Yun-Ching Fua,b, Ching-Shiang Chia,b, Sui-Chu Yinc, Betau Hwangb,d, Yung-Tsung Chiuc and Shih-Lan Hsu*,b,c

aDepartment of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
bInstitute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
cDepartment of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, ROC
dDepartment of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

* Corresponding author. Department of Education and Research, Taichung Veterans General Hospital, 160 Section 3, Chung-Kang Road, Taichung 40705, Taiwan, ROC. Tel.: +886-4-2359-2525x4039; fax: +886-4-23592705. Email address: h2326{at}vghtc.vghtc.gov.tw

Objective: Norepinephrine (NE)-induced apoptosis in cardiomyocytes is an important cause of heart failure. Previous studies revealed that reactive oxygen species (ROS) are involved in apoptosis. Tumor necrosis factor-{alpha} (TNF), a well-known mediator that stimulates apoptosis, is not only produced by macrophages but also by cardiomyocytes. Until now, the role of TNF and its relationship to ROS in NE-induced apoptosis of cardiomyocytes have never been investigated. Methods: Neonatal rat cardiomyocytes were treated with various concentrations of NE. Apoptosis of cardiomyocytes was determined using the TUNEL assay. The level of secreted TNF was measured by ELISA and TNF mRNA expression was determined by semiquantitative reverse transcriptional polymerase chain reaction. Caspase activity was measured by a fluorogenic protease assay kit. Anti-TNF antibodies, caspase inhibitors and antioxidants (N-acetyl-L-cysteine or vitamin C) were added to determine if they could inhibit the apoptotic effect of NE. Results: NE induced apoptosis of cardiomyocytes in a dose- and time-dependent manner. NE up-regulated TNF mRNA expression and increased TNF secretion and caspase-2,-3,-6, and -9 activities. A neutralizing anti-TNF antibody and caspase-2 and -3 inhibitors significantly attenuated NE-induced apoptosis. Antioxidants completely abrogated NE-induced TNF secretion, caspase activation, and apoptotic death. Conclusion: NE induced apoptosis in neonatal rat cardiomyocytes through a ROS–TNF–caspase signaling pathway.

KEYWORDS Apoptosis; Cardiomyocytes; Norepinephrine; Reactive oxygen species; Tumor necrosis factor

Time for primary review 19 days


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