© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Tumor necrosis factor-
enhances hypoxia–reoxygenation-mediated apoptosis in cultured human coronary artery endothelial cells: critical role of protein kinase C
Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd., P.O. Box 100277 JHMHC, Gainesville FL 32610, USA
* Corresponding author. Tel.: +1-352-379-4160; fax: +1-352-379-4161. E-mail address: mehta@medmac.ufl.edu (J.L. Mehta)
Background: Ischemia and tumor necrosis factor-
(TNF) released during ischemia both cause apoptosis and necrosis of myocardial tissues. Since endothelium may be critically important in determination of cardiac function, we examined the interaction between TNF and hypoxia–reoxygenation with regard to induction of apoptosis and underlying signaling pathway in cultured human coronary artery endothelial cells (HCAECs). Methods and results: HCAECs were cultured and exposed to hypoxia alone, hypoxia–reoxygenation, TNF alone, TNF plus hypoxia–reoxygenation, or TNF only during the period of reoxygenation. Apoptosis was evaluated by transmission electron microscopy, DNA nick-end labeling and DNA laddering. Hypoxia alone caused modest time-dependent apoptosis of cultured HCAECs, and reoxygenation increased the number of apoptotic cells (P<0.01 vs. hypoxia alone). TNF induced concentration-dependent apoptosis, and enhanced reoxygenation-mediated apoptosis in cultured HCAECs (P<0.01 vs. hypoxia–reoxygenation alone). As expected, monoclonal antibody to TNF significantly blocked the pro-apoptotic effect of TNF-induced apoptosis (P<0.01). TNF-induced apoptosis was found to be associated with marked activation of protein kinase C (PKC), and pretreatment of cells with a specific PKC inhibitor markedly reduced TNF-mediated PKC activity and apoptosis. Conclusion: These observations indicate that hypoxia alone causes modest apoptosis, reoxygenation increases apoptosis beyond that caused by hypoxia in cultured HCAECs. TNF alone causes apoptosis, and further enhances apoptosis caused by hypoxia–reoxygenation. The activation of PKC plays a critical role in TNF-induced apoptosis of cultured HCAECs.
KEYWORDS Apoptosis; Endothelial cell; Hypoxia; Reoxygenation; Tumor necrosis factor-
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