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(Circulation. 2003;107:2102.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Low-Density Lipoprotein in Hypercholesterolemic Human Plasma Induces Vascular Endothelial Cell Apoptosis by Inhibiting Fibroblast Growth Factor 2 Transcription

Chu-Huang Chen, MD, PhD; Tao Jiang, PhD; Jun-Hai Yang, PhD; Wei Jiang, MD; Jonathan Lu, MD; Gopal K. Marathe, PhD; Henry J. Pownall, PhD; Christie M. Ballantyne, MD; Thomas M. McIntyre, PhD; Philip D. Henry, MD; Chao-Yuh Yang, PhD

From the Departments of Medicine (C.-H.C., T.J., W.J., J.L., H.J.P., C.M.B., P.D.H., C.-Y.Y.) and Ophthalmology (J.-H.Y.), Baylor College of Medicine, Houston, Tex, and the Department of Internal Medicine (G.K.M., T.M.M.), University of Utah, Salt Lake City.

Correspondence to Chu-Huang Chen, MD, PhD, MS A-601, Department of Medicine, Baylor College of Medicine, 6565 Fannin St, Houston, Texas 77030. E-mail cchen{at}bcm.tmc.edu

Background— Apoptosis of vascular endothelial cells (ECs) can be induced in vitro by experimentally modified LDL. Description of proapoptotic circulating lipoproteins may significantly enhance understanding of atherothrombosis pathophysiology.

Methods and Results— Fast protein liquid chromatography of LDL samples from 7 asymptomatic, hypercholesterolemic patients yielded subfractions L₁–L₅ in increasing electronegativity. L₄ and L₅ were not detectable or collectible in normolipidemic samples. In bovine aortic EC cultures, L₅ induced marked apoptosis and L₄ had a mild effect, whereas hypercholesterolemic or normolipidemic L₁–L₃ had negligible effects. Compared with copper-oxidized LDL, L₅ was only mildly oxidized, although its propensity to form conjugated dienes in response to copper exceeded that of other subfractions. L₅-induced apoptosis was associated with suppressed fibroblast growth factor 2 (FGF-2) transcription, as assessed by nuclear run-on analysis. Degrading platelet-activating factor (PAF)-like lipids in L₅ by a recombinant PAF acetylhydrolase prevented both FGF-2 downregulation and apoptosis. Furthermore, the ability of L₅ lipid extract to induce calcium influx into neutrophils was lost after pretreatment of the extract with PAF acetylhydrolase. FGF-2 supplementation, PAF receptor (PAFR) blockade with WEB-2086, and inactivation of PAFR-coupled G_i protein with pertussis toxin all effectively attenuated L₅-induced apoptosis.

Conclusions— Our findings indicate that a highly electronegative, mildly oxidized LDL subfraction present in human hypercholesterolemic but not normolipidemic plasma can induce apoptosis in cultured ECs. The evidence that a freshly isolated LDL species modulates transcription of FGF-2 may provide a physiological insight into the mechanism of vascular EC apoptosis in hypercholesterolemia.

Key Words: lipoproteins • endothelium • apoptosis • growth substances • phospholipids

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