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(Circulation. 2001;104:588.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Oxidized Low-Density Lipoprotein Downregulates Endothelial Basic Fibroblast Growth Factor Through a Pertussis Toxin-Sensitive G-Protein Pathway

Mediator Role of Platelet-Activating Factor-Like Phospholipids

Po-Yuan Chang, MD, PhD; Sherry Luo, BS; Tao Jiang, PhD; Yuan-Teh Lee, MD, PhD; Shao-Chun Lu, PhD; Philip D. Henry, MD; Chu-Huang Chen, MD, PhD

From the Department of Medicine, Baylor College of Medicine, Houston, Tex (P.-Y.C., S.L., T.J., P.D.H., C.-H.C.); and the Departments of Internal Medicine (P.-Y.C., Y.-T.L.) and Biochemistry (S.-C.L.), National Taiwan University Medical School, Taipei, Taiwan.

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

Background— Oxidized LDL (oxLDL) inhibits angiogenesis in part by downregulating endothelial basic fibroblast growth factor (bFGF). To determine the mechanism of the downregulation, we investigated the signal transduction pathway involving potential phospholipid mediators.

Methods and Results— Cultured bovine aortic endothelial cells were incubated with PBS (lipoprotein-free control), LDL, or copper oxLDL under serum-free conditions. At 24 hours, oxLDL (50 µg/mL) decreased bFGF mRNA (Northern blot), bFGF protein (Western blot and ELISA), and concomitant DNA synthesis, all by 40% to 50% compared with PBS. LDL had no effect. Pretreating the cells with 100 ng/mL pertussis toxin (PTX) for 18 hours before oxLDL exposure almost completely blocked the inhibitory effects of oxLDL. In contrast, inhibiting other major cellular signal transduction pathways with PD-98059 (mitogen-activated protein kinase kinase inhibitor), HA-1004 (inhibitor of cGMP- and cAMP-dependent protein kinase), or Ro-31-8220 (protein kinase C inhibitor) or chelating intracellular Ca²⁺ with BAPTA-AM failed to attenuate any of the oxLDL effects assayed. Addition to the cultures of WEB 2086, a specific antagonist of the PTX-sensitive G protein–coupled platelet-activating factor (PAF) receptor, blocked the action of oxLDL. Whereas PAF dispersed in the culture medium failed to produce oxLDL-like effects, degradation of PAF and PAF-like phospholipids accumulated in oxLDL with a recombinant human PAF acetylhydrolase eliminated the inhibitory effects of oxLDL on bFGF expression and DNA synthesis.

Conclusions— OxLDL suppresses endothelial bFGF expression and DNA synthesis through a PTX-sensitive heterotrimeric G-protein pathway involving mediator phospholipids similar, but not identical, to PAF.

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

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