Induction of basic fibroblast growth factor mRNA and protein synthesis in smooth muscle cells by cholesteryl ester enrichment and 25-hydroxycholesterol.
Basic fibroblast growth factor (bFGF) is a potent smooth muscle cell mitogen. Smooth muscle cell and macrophage-derived foam cells, resulting from cholesteryl ester accretion, are hallmark characteristics of atherosclerosis. We wanted to determine if bFGF synthesis is altered during cholesteryl ester accumulation in smooth muscle cells. Cholesteryl ester enrichment causes a 3-fold increase in bFGF in cellular lysates and a 3-fold increase in steady state mRNA levels for bFGF, as compared with control cells. Conditioned media from cholesteryl ester-enriched smooth muscle cells contains 6 times more mitogenic activity than conditioned media from control cells; this activity is neutralized by an antibody directed against bFGF but not by an antibody directed against platelet-derived growth factor. These results suggest that cholesteryl ester enrichment also enhances bFGF release. Since oxysterols have been implicated in the pathogenesis of atherosclerosis, we determined if oxysterols could affect bFGF production and release. 25-Hydroxycholesterol also increases the release of bFGF-like mitogens from smooth muscle cells, as well as increasing mRNA transcript levels for bFGF. Cholesteryl ester enrichment and 25-hydroxycholesterol did not promote bFGF release secondary to cell injury. In conclusion, these data define a basic mechanism for smooth muscle cell hyperplasia during atherogenesis involving the generation of bFGF by smooth muscle cell-derived foam cells.
Kraemer
R
R
Department of Pathology, Cornell University Medical College, New York, New York 10021.
Pomerantz
K B
KB
Joseph-Silverstein
J
J
Hajjar
D P
DP
D000818:Animals; D000906:Antibodies; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D015152:Blotting, Northern; D002417:Cattle; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D004261:DNA Replication; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008075:Lipoproteins, HDL / Q000097:blood / Q000302:isolation & purification; D008077:Lipoproteins, LDL / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011817:Rabbits; D013936:Thymidine / Q000378:metabolism
D000906:Antibodies; D002788:Cholesterol Esters; D017077:Culture Media, Conditioned; D006888:Hydroxycholesterols; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; C007997:25-hydroxycholesterol; D007770:L-Lactate Dehydrogenase; D013936:Thymidine