Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide.
Angiotensin II (Ang II) importantly contributes to the pathobiology of atherosclerosis. Since endothelial injury is a key event early in the pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure endothelial cells by activation of cellular suicide pathways leading to apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by ELISA specific for histone-associated DNA fragments and confirmed by DNA laddering and nuclear staining. Ang II dose-dependently induced apoptosis of HUVECs. Simultaneous blockade of both the AT1 and AT2 receptor prevented Ang II-induced apoptosis, whereas each individual receptor blocker alone was not effective. Selective agonistic stimulation of the AT2 receptor also dose-dependently induced apoptosis. Ang II-mediated as well as selective AT2 receptor stimulation-mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program. Specific inhibition of caspase-3 activity abrogated Ang II-induced apoptosis. In addition, the NO donors sodium nitroprusside and S-nitrosopenicillamine completely inhibited Ang II-induced apoptosis and eliminated caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of the caspase cascade, the central downstream effector arm executing the cell death program. NO completely abrogated Ang II-induced apoptosis by interfering with the activation of the caspase cascade.
Dimmeler
S
S
Department of Internal Medicine IV, University of Frankfurt, Germany. Dimmeler@em.uni-frankfurt.de
Rippmann
V
V
Weiland
U
U
Haendeler
J
J
Zeiher
A M
AM
D000804:Angiotensin II / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000804:Angiotensin II; D009599:Nitroprusside; D009569:Nitric Oxide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases