This Article Full Text Full Text (PDF) Data Supplement Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spyridopoulos, I. Articles by Karsch, K. R. Search for Related Content PubMed PubMed Citation Articles by Spyridopoulos, I. Articles by Karsch, K. R. Related Collections Apoptosis Calcium cycling/excitation-contraction coupling Cell signalling/signal transduction Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:439.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Alcohol Enhances Oxysterol-Induced Apoptosis in Human Endothelial Cells by a Calcium-Dependent Mechanism

Ioakim Spyridopoulos; Jörg Wischhusen; Björn Rabenstein; Petra Mayer; Dorothea I. Axel; Kai-Uwe Fröhlich; Karl R. Karsch

From the Departments of Cardiology (I.S., J.W., P.M., D.I.A., K.R.K.) and Physiological Chemistry (J.W., K.-U.F.), University of Tübingen, Tübingen, and the Institute of Chemistry (B.R.), Free University of Berlin, Berlin, Germany.

Correspondence to Ioakim Spyridopoulos, MD, Department of Cardiology and Cardiovascular Research, Medizinische Klinik III, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany. E-mail ioakim_s{at}hotmail.com

Abstract—Controversy exists about the net effect of alcohol on atherogenesis. A protective effect is assumed, especially from the tannins and phenolic compounds in red wine, owing to their inhibition of low density lipoprotein (LDL) oxidation. However, increased atherogenesis occurs in subjects with moderate to heavy drinking habits. The purpose of this study was to investigate the influence of alcohol in combination with oxysterols on the endothelium. Cultured human arterial endothelial cells (HAECs) served as an in vitro model to test the cellular effects of various oxysterols. Oxysterols (7ß-hydroxycholesterol, 7-ketocholesterol, and cholesterol-5,6-epoxides), which are assumed to be the most toxic constituents of oxidized LDL, induced apoptosis in HAECs through calcium mobilization followed by activation of caspase-3. Ethanol, methanol, isopropanol, tert-butanol, and red wine all potentiated oxysterol-induced cell death up to 5-fold, paralleled by further induction of caspase-3. The alcohol effect occurred in a dose-dependent manner and reached a plateau at 0.05% concentration. Alcohol itself did not affect endothelial cell viability, nor did other solvents such as dimethyl sulfoxide mimic the alcohol effect. So far as the physiologically occurring oxysterols are concerned, this effect was apparent only for oxysterols oxidized at the steran ring. The possibility of alcohol facilitating the uptake of oxysterols into the cell was not supported by the data from an uptake study with radiolabeled compounds. Finally, alcohol in combination with oxysterols did cause a dramatic increase in cytosolic calcium influx. Blockage of calcium influx by the calcium channel blocker aurintricarboxylic acid or the calcium chelator ethylene glycol-bis(ß-aminoethyl ether)-N,N,N’,N’-tetraacetic acid abrogated the alcohol-mediated enhancement of oxysterol toxicity. We describe for the first time a mechanistic concept explaining possible adverse effects of alcohol in conjunction with physiologically occurring oxysterols on atherogenesis.

Key Words: atherosclerosis • apoptosis • oxysterols • calcium • caspase-3

This article has been cited by other articles:

				M. E. Jung, M. B. Gatch, and J. W. Simpkins Estrogen Neuroprotection Against the Neurotoxic Effects of Ethanol Withdrawal: Potential Mechanisms Experimental Biology and Medicine, January 1, 2005; 230(1): 8 - 22. [Abstract] [Full Text] [PDF]