Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.
Oxidatively modified low density lipoprotein (LDL) exhibits several potentially atherogenic properties, and inhibition of LDL oxidation in rabbits decreases the rate of the development of atherosclerotic lesions. In vitro studies have suggested that cellular lipoxygenases may be involved in LDL oxidation, and we have shown previously that 15-lipoxygenase and oxidized LDL are present in rabbit atherosclerotic lesions. We now report that epitopes of oxidized LDL are also found in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions. Using in situ hybridization and immunostaining techniques, we also report that 15-lipoxygenase mRNA and protein colocalize to the same macrophage-rich areas. Moreover, these same lesions express abundant mRNA for the acetyl LDL receptor but no detectable mRNA for the LDL receptor. We suggest that atherogenesis in human arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase, leading to subsequent enhanced macrophage uptake, partly by way of the acetyl LDL receptor.
Ylä-Herttuala
S
S
Department of Medicine, University of California, San Diego 92093.
Rosenfeld
M E
ME
Parthasarathy
S
S
Sigal
E
E
Särkioja
T
T
Witztum
J L
JL
Steinberg
D
D
D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics*; D015815:Cell Adhesion Molecules; D015870:Gene Expression; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009693:Nucleic Acid Hybridization; D015347:RNA Probes; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000276:immunology; D051116:Receptors, Scavenger
D015815:Cell Adhesion Molecules; D015347:RNA Probes; D012333:RNA, Messenger; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D001093:Arachidonate 15-Lipoxygenase