DNA fragmentation and ultrastructural changes of degenerating cells in atherosclerotic lesions and smooth muscle cells exposed to oxidized LDL in vitro.
Degeneration of smooth muscle cells in the fibrous cap of atherosclerotic lesions is an important factor in plaque rupture. Recent studies have suggested that many plaque cells are in a process of apoptosis as determined by positive deoxyribonucleotide-transferase-mediated dUTP end labeling. In this study, we demonstrate the existence of a colocalization between deoxyribonucleotide-transferase-mediated dUTP end labeling-positive smooth muscle cells and oxidized LDL immunoreactivity in human carotid plaques. Oxidized LDL was found to induce deoxyribonucleotide-transferase-mediated dUTP end labeling positivity in cultured human smooth muscle cells, but only in the presence of tumor necrosis factor-alpha and interferon-gamma. Electron microscopic analysis of cultured smooth muscle cells exposed to oxidized LDL in the absence of cytokines demonstrated cytoplasmic swelling and disruption of the plasma membrane, suggesting cell death by oncosis. Cells exposed to both oxidized LDL and cytokines were characterized by chromatin and cytoplasmic condensation compatible with cell death by apoptosis. These findings further support the notion that oxidized lipids play a role in plaque cell death.
Jovinge
S
S
King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden. Stefan.Jovinge@medks.ki.se
Crisby
M
M
Thyberg
J
J
Nilsson
J
J
D001161:Arteriosclerosis / Q000473:pathology*; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects*; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000633:toxicity*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D003856:Deoxyuracil Nucleotides; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C027078:deoxyuridine triphosphate; D007371:Interferon-gamma