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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:908.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Phospholipid Transfer Protein Augments Apoptosis in THP-1–Derived Macrophages Induced by Lipolyzed Hypertriglyceridemic Plasma

Andreas Wehinger; Ivan Tancevski; Wilfried Schgoer; Philipp Eller; Kathrin Hochegger; Maria Morak; Albin Hermetter; Andreas Ritsch; Josef R. Patsch; Bernhard Foeger

From the Department of Internal Medicine (A.W., I.T., W.S., P.E., K.H., A.R., J.R.P., B.F.), Medical University Innsbruck, Innsbruck, Austria; the Department of Biochemistry (M.M., A.H.), Technische Universität Graz, Graz, Austria; and the Department of Internal Medicine (B.F.), Landeskrankenhaus Bregenz, Bregenz, Austria.

Correspondence to Bernhard Foeger, Department of Internal Medicine, Landeskrankenhaus Bregenz, Carl-Pedenz-Strasse 2, 6900 Bregenz; Austria. E-mail bernhard.foeger{at}lkhb.at

Objective— Lipolysis of triglyceride-rich lipoproteins (TGRLPs) generates phospholipid-rich surface remnants and induces cytotoxic effects in adjacent vascular cells. We hypothesized that by integrating surface remnants into HDL, phospholipid transfer protein (PLTP) alleviates cytotoxicity.

Methods and Results— To test this hypothesis and gain insight into cytotoxicity during the postprandial phase in vivo, we injected normo-TG and hyper-TG human volunteers after a standardized fat meal (postprandial sample) with heparin, thereby stimulating lipolysis (postprandial heparinized sample). Incubation of (primary) human macrophages and primary human endothelial cells with postprandial heparinized hyper-TG plasma induced pronounced cytotoxic effects that were dose dependent on the TG content of the sample. No such effects were seen with normo-TG and postprandial hyper-TG plasma. In vitro lipolysis of VLDL and chylomicrons indicated that both lipoprotein fractions can cause cytotoxicity. Interestingly, in experiments with THP-1–derived macrophages stably transfected with PLTP, PLTP substantially augmented both net phospholipid uptake and apoptotic cell death due to postprandial heparinized hyper-TG plasma. We observed that activation of caspase-3/7, poly-ADP-ribose polymerase, and enhanced bioactivity of acid sphingomyelinase may all contribute to this augmented apoptosis.

Conclusions— Our data show that lipolysis of TGRLPs and their remodelling by PLTP interact to disturb cellular phospholipid flux and intracellular signaling processes, ultimately leading to apoptosis in human macrophages and endothelial cells.

Our study focuses on the link between postprandial lipolysis of TGRLP and vessel wall cellular toxicity. We demonstrate that human macrophages and endothelial cells show decreased viability in the presence of high lipolyzed TGRLP and that enhanced PLTP-activity augments this cytotoxicity by modulating cellular phospholipid flux and signalling events including caspase 3/7, PARP, and acid SMase.

Key Words: phospholipid transfer protein • apoptosis • human macrophages • in vivo lipolysis • hypertriglyceridemia • triglyceride-rich lipoproteins