Effects of glycated low-density lipoprotein on cell viability, proliferation, and growth factors of mouse embryo fibroblasts.
The predominant cause of death in diabetic patients is atherosclerotic coronary artery disease (CAD). Major gross cellular changes in the vascular wall of persons with CAD include endothelial injury and foam cell formation, as well as smooth muscle cell and fibroblast proliferation. This study examined the effects of glycated low density lipoprotein (glyLDL), a biochemical marker of diabetes, on cell viability, proliferation, and the expression of multiple growth factors in mouse embryo fibroblasts (MEF). The results demonstrated that exposure to ≥150 μg/mL of glyLDL for 24 h or 100 μg/mL of glyLDL for ≥48 h either significantly reduced cell viability or increased DNA fragmentation in MEF. GlyLDL treatment (25-100 μg/mL for up to 12 h) significantly increased the abundance of proliferating cell nuclear antigen (PCNA) and achieved a peak after 4 h exposure to glyLDL. Abundances of fibroblast growth factor-basic (FGF), transforming growth factor-β (TGF), and platelet-derived growth factor-A (PDGF) in MEF reached maximal levels after 2 h exposure to 50 μg/mL of glyLDL. The maximal increase of vascular endothelial growth factor (VEGF) was detected in MEF after 4 h of exposure to 50 μg/mL of glyLDL. Inhibitors for FGF (AZD4547), VEGF, or PDGF receptors (Axitinib), but not that for TGF receptor (LY364947), significantly decreased the abundance of (PCNA) in endothelial cells. The findings suggest that early exposure to a low dosage of glyLDL transiently increases the proliferation of MEF through the upregulation of FGF, VEGF, and (or) PDGF, and prolonged exposure to high concentrations of glyLDL reduced cell viability, which possibly accelerates atherogenesis under diabetic condition.
Department of Internal Medicine, Health Sciences Centre, University of Manitoba, 820 Sherbrooke Street, Winnipeg, MB R3T 2N2, Canada.
Ruozhi
R
Zhao
Xueping
X
Xie
Garry X
GX
Shen
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017127:Glycation End Products, Advanced; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093844:Glycated Proteins
D005346:Fibroblast Growth Factors; D017127:Glycation End Products, Advanced; D036341:Intercellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C075278:platelet-derived growth factor A; C467480:vascular endothelial growth factor A, mouse