(Circulation. 2000;101:171.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Oxidized Low-Density Lipoproteins Inhibit Endothelial Cell Proliferation by Suppressing Basic Fibroblast Growth Factor Expression
Presented in abstract form at the Biomedicine 96 Meeting of the American Association of Physicians, Washington, DC, May 3–6, 1996, and the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-277).
From the Department of Medicine, Baylor College of Medicine, Houston, Tex (C.-H.C., W.J., D.P.V., S.L., P.D.H.), and the Department of Internal Medicine, National Taiwan University Hospital, Taipei (T.-R.L., Y.-T.L.).
Correspondence to Chu-Huang Chen, MD, PhD, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, TX 77030. E-mail cchen{at}bcm.tmc.edu
Background—Hyperlipidemia inhibits proliferation of endothelial cells (ECs) in culture and angiogenesis in vivo and in arterial explants. Elucidation of the mechanisms may suggest novel therapies against atherosclerosis.
Methods and Results—Basic fibroblast growth factor (bFGF) expression and mitogenic effects were assessed in bovine aortic ECs incubated with oxidized LDL (ox-LDL). Compared with native LDL and lipoprotein-free controls, ox-LDL reduced bFGF mRNA levels in a time- and concentration-dependent manner, 100 µg/mL producing a maximum reduction of 40% to 50% within 24 to 48 hours. There were commensurate reductions in intracellular and extracellular bFGF concentrations, DNA and total RNA syntheses, and cell replication. FGF receptor 1 and ß-actin mRNA levels were unchanged. Ox-LDL accelerated bFGF mRNA degradation in actinomycin D–treated cells. However, inhibition of bFGF expression by ox-LDL was attenuated by cyclohexamide, indicating a requirement for continuous new protein synthesis for posttranscriptional destabilization. Reduced syntheses of DNA and total RNA were completely restored by bFGF but not by vascular endothelial growth factor. Inhibition of total RNA synthesis achieved by exposing cells to a bFGF-neutralizing antibody was similar in magnitude to that induced by ox-LDL.
Conclusions—Cytotoxic effects of ox-LDL on ECs are attributable in part to suppression of bFGF expression.
Key Words: lipoproteins • growth substances • endothelium • genes • angiogenesis
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