Published Online
on April 14, 2003

A more recent version of this article appeared on April 29, 2003

This Article Full Text (PDF) All Versions of this Article: 107/16/2102    most recent 01.CIR.0000065220.70220.F7v1 Alert me when this article is cited Alert me if a correction is posted 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 Chen, C.-H. Articles by Yang, C.-Y. Search for Related Content PubMed PubMed Citation Articles by Chen, C.-H. Articles by Yang, C.-Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Medline Plus Health Information Cholesterol Related Collections Apoptosis Gene expression Gene regulation Growth factors/cytokines Lipid and lipoprotein metabolism

Submitted on December 19, 2002
Accepted on February 10, 2003

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, and 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.

^* To whom correspondence should be addressed. 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

This article has been cited by other articles:

				J. L. Kielczewski, Y. P.R. Jarajapu, E. L. McFarland, J. Cai, A. Afzal, S. Li Calzi, K. H. Chang, T. Lydic, L. C. Shaw, J. Busik, et al. Insulin-Like Growth Factor Binding Protein-3 Mediates Vascular Repair by Enhancing Nitric Oxide Generation Circ. Res., October 23, 2009; 105(9): 897 - 905. [Abstract] [Full Text] [PDF]

				C.-H. Chen, R. A.F. Dixon, L.-Y. Ke, and J. T. Willerson Vascular Progenitor Cells in Diabetes Mellitus: Roles of Wnt Signaling and Negatively Charged Low-Density Lipoprotein Circ. Res., May 8, 2009; 104(9): 1038 - 1040. [Full Text] [PDF]

				J. Lu, J.-H. Yang, A. R. Burns, H.-H. Chen, D. Tang, J. P. Walterscheid, S. Suzuki, C.-Y. Yang, T. Sawamura, and C.-H. Chen Mediation of Electronegative Low-Density Lipoprotein Signaling by LOX-1: A Possible Mechanism of Endothelial Apoptosis Circ. Res., March 13, 2009; 104(5): 619 - 627. [Abstract] [Full Text] [PDF]

				C. Bancells, S. Benitez, M. Jauhiainen, J. Ordonez-Llanos, P. T. Kovanen, S. Villegas, J. L. Sanchez-Quesada, and K. Oorni High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level J. Lipid Res., March 1, 2009; 50(3): 446 - 455. [Abstract] [Full Text] [PDF]

				M. Pirro, G. Schillaci, P. F. Romagno, M. R. Mannarino, F. Bagaglia, R. Razzi, L. Pasqualini, G. Vaudo, and E. Mannarino Influence of Short-term Rosuvastatin Therapy on Endothelial Progenitor Cells and Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2009; 14(1): 14 - 21. [Abstract] [PDF]

				M. Pirro, F. Bagaglia, L. Paoletti, R. Razzi, and M. R. Mannarino Review: Hypercholesterolemia-associated endothelial progenitor cell dysfunction Therapeutic Advances in Cardiovascular Disease, October 1, 2008; 2(5): 329 - 339. [Abstract] [PDF]

				M. A. Medina Hyperhomocysteinemia and Occlusive Vascular Disease: An Emergent Role for Fibroblast Growth Factor 2 Circ. Res., April 25, 2008; 102(8): 869 - 870. [Full Text] [PDF]

				P.-Y. Chang, S.-C. Lu, C.-M. Lee, Y.-J. Chen, T. A. Dugan, W.-H. Huang, S.-F. Chang, W. S.L. Liao, C.-H. Chen, and Y.-T. Lee Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation Circ. Res., April 25, 2008; 102(8): 933 - 941. [Abstract] [Full Text] [PDF]

				D. Tang, J. Lu, J. P. Walterscheid, H.-H. Chen, D. A. Engler, T. Sawamura, P.-Y. Chang, H. J. Safi, C.-Y. Yang, and C.-H. Chen Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1 J. Lipid Res., January 1, 2008; 49(1): 33 - 47. [Abstract] [Full Text] [PDF]

				J. Lu, W. Jiang, J.-H. Yang, P.-Y. Chang, J. P. Walterscheid, H.-H. Chen, M. Marcelli, D. Tang, Y.-T. Lee, W. S.L. Liao, et al. Electronegative LDL Impairs Vascular Endothelial Cell Integrity in Diabetes by Disrupting Fibroblast Growth Factor 2 (FGF2) Autoregulation Diabetes, January 1, 2008; 57(1): 158 - 166. [Abstract] [Full Text] [PDF]

				J. Cheng, R. Cui, C.-H. Chen, and J. Du Oxidized Low-Density Lipoprotein Stimulates p53-Dependent Activation of Proapoptotic Bax Leading to Apoptosis of Differentiated Endothelial Progenitor Cells Endocrinology, May 1, 2007; 148(5): 2085 - 2094. [Abstract] [Full Text] [PDF]

				C.-H. Chen and J. P. Walterscheid Plaque Angiogenesis Versus Compensatory Arteriogenesis in Atherosclerosis Circ. Res., October 13, 2006; 99(8): 787 - 789. [Full Text] [PDF]

				G. K. Marathe, C. Johnson, S. D. Billings, M. D. Southall, Y. Pei, D. Spandau, R. C. Murphy, G. A. Zimmerman, T. M. McIntyre, and J. B. Travers Ultraviolet B Radiation Generates Platelet-activating Factor-like Phospholipids underlying Cutaneous Damage J. Biol. Chem., October 21, 2005; 280(42): 35448 - 35457. [Abstract] [Full Text] [PDF]

				J. W. Choi and S. K. Kim Relationships of Soluble APO-1 (Fas/CD95) Concentrations, Obesity, and Serum Lipid Parameters in Healthy Adults Ann. Clin. Lab. Sci., January 1, 2005; 35(3): 290 - 296. [Abstract] [Full Text] [PDF]

				F. Bonin, S. D. Ryan, L. Migahed, F. Mo, J. Lallier, D. J. Franks, H. Arai, and S. A. L. Bennett Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I {alpha}2 Catalytic Subunit J. Biol. Chem., December 10, 2004; 279(50): 52425 - 52436. [Abstract] [Full Text] [PDF]

				P.-Y. Chang, S.-C. Lu, T.-C. Su, S.-F. Chou, W.-H. Huang, J. D. Morrisett, C.-H. Chen, C.-S. Liau, and Y.-T. Lee Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation J. Lipid Res., November 1, 2004; 45(11): 2116 - 2122. [Abstract] [Full Text] [PDF]