Oxidized low-density lipoproteins inhibit endothelial cell proliferation by suppressing basic fibroblast growth factor expression.
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.


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 microg/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 beta-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.
Chen
C H
CH
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. cchen@bcm.tmc.edu
Jiang
W
W
Via
D P
DP
Luo
S
S
Li
T R
TR
Lee
Y T
YT
Henry
P D
PD
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008077:Lipoproteins, LDL; D008222:Lymphokines; D019384:Nucleic Acid Synthesis Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C099252:oxidized low density lipoprotein; D016222:Fibroblast Growth Factor 2; D003609:Dactinomycin; D012313:RNA; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1