Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.
Oxidation of low density lipoprotein (LDL) enhances its atherogenicity, and inhibition of such oxidation decreases the rate of progression of atherosclerotic lesions. The mechanism of LDL oxidation in vivo remains uncertain, but in vitro studies have suggested that cellular lipoxygenases may play a role by initiating lipid peroxidation in LDL. In situ hybridization studies using a 15-lipoxygenase riboprobe and immunostaining using antibodies against 15-lipoxygenase showed strongly positive reactivity largely confined to macrophage-rich areas of atherosclerotic lesions. Polymerase chain reaction with 15-lipoxygenase-specific oligonucleotides and restriction enzyme digestions of the amplified fragment were used to confirm the presence of 15-lipoxygenase message in the reverse-transcribed lesion mRNA. Immunostaining with antibodies reactive with oxidized LDL (but not with native LDL) indicated that the lipoxygenase colocalizes with epitopes of oxidized LDL, compatible with a role for macrophage lipoxygenase in the oxidation of LDL in vivo. Since oxidized LDL is chemotactic for blood monocytes, early lesions might progress at a markedly accelerated rate because of further recruitment of more monocytes which, in turn, would increase further the rate of oxidation of LDL. These data suggest that therapy targeted to block macrophage lipoxygenase activity might decrease the rate of development of atherosclerotic lesions.
Department of Medicine, University of California-San Diego, La Jolla 92093.
S
S
Ylä-Herttuala
M E
ME
Rosenfeld
S
S
Parthasarathy
C K
CK
Glass
E
E
Sigal
J L
JL
Witztum
D
D
Steinberg
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D001091:Arachidonate Lipoxygenases / Q000235:genetics*; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology*; D001483:Base Sequence; D003001:Cloning, Molecular; D000939:Epitopes / Q000032:analysis*; D006801:Humans; D007124:Immunoenzyme Techniques; D008077:Lipoproteins, LDL / Q000032:analysis* / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology*; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D011817:Rabbits
D000939:Epitopes; D008077:Lipoproteins, LDL; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D001091:Arachidonate Lipoxygenases; D001093:Arachidonate 15-Lipoxygenase