From the Department of Internal Medicine IV (D.H.W., J.H., A.M.Z., S.D.),
Division of Cardiology, University of Frankfurt, Germany, and Department of
Nephrology (J.G.), University of Würzburg, Germany.
Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Zeiher{at}em.uni-frankfurt.de
Abstract
Background—Several experimental
and clinical studies suggest that cyclosporin A (CSA) treatment reduces
transplant atherosclerosis. Because oxidized LDL
(oxLDL) is believed to play a key role in the development of
atherogenesis, causing injury to the endothelium, and
has been shown to induce apoptosis of
endothelial cells, we investigated whether CSA inhibits
oxLDL-induced apoptosis.
Methods and Results—Apoptosis was induced in human
umbilical venous endothelial cells (HUVECs) by
incubation of 10 µg/mL oxLDL for 18 hours. Coincubation with CSA dose
dependently decreased oxLDL-induced apoptosis, with a maximal
effect at 10 µmol/L. In addition, tumor necrosis factor-
Conclusions—OxLDL induces dysfunction of the mitochondrial
membrane, leading to cytochrome C release into the cytosol, and thereby
stimulates apoptosis of human endothelial
cells. Apoptosis suppression by CSA correlates with the
prevention of mitochondrial dysfunction and thus indicates the
importance of mitochondrial destabilization in oxLDL-induced
apoptosis signaling. The inhibition of apoptosis by CSA
might preserve the function of the endothelium and may
at least in part contribute to the antiatherogenic effects of CSA in
transplant atherosclerosis.
© 1998 American Heart Association, Inc.
Brief Rapid Communication
Cyclosporin A Inhibits Apoptosis of Human Endothelial Cells by Preventing Release of Cytochrome C From Mitochondria
–
and angiotensin II–induced apoptosis was
significantly prevented by CSA treatment, suggesting a general
apoptosis-suppressive effect of CSA. CSA has been shown to
inhibit disruption of the mitochondrial membrane function, which plays
a key role in apoptosis induction. Indeed, oxLDL treatment
triggered the release of cytochrome C from the mitochondria into the
cytosol, indicating disturbance of the mitochondrial membrane.
CSA (10 µmol/L) completely inhibited the oxLDL-induced release
of cytochrome C. Moreover, tumor necrosis factor-– and
angiotensin II–induced cytochrome C release was prevented
by CSA treatment.
Key Words: cells • apoptosis • endothelium • lipoproteins • atherosclerosis • cyclosporin A
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