Increased uptake of folate conjugates by activated macrophages in experimental hyperlipemia.
In the pathogenesis of atherosclerosis, macrophages become activated and play a crucial role in plaque formation. Activated synovial macrophages have recently been shown to express receptors for folic acid. We have determined whether activated macrophages also over-express folate receptor (FR) in atherosclerosis. Most normal cells express little or no FR, and, if FR is present on activated macrophages, folate-linked compounds and drugs could be selectively targeted to those cells that do express FR. To evaluate the FR on macrophages of atherosclerotic animals, golden Syrian hamsters were maintained on a hyperlipidemic diet until extensive vascular lesions had developed. Uptake of folic acid conjugated to fluorescent tags was then examined in tissue fragments from lesion-prone areas, and peritoneal activated macrophages were harvested from the same animals. Spectrofluorimetric and fluorescence microscopic analyses showed a significantly greater uptake of folate-conjugates by peritoneal macrophages of hyperlipidemic hamsters compared with those of hamsters fed a normal or folate-deficient diet. Systemically administered folate-fluorescent conjugates were found to accumulate as bright spots in protrusions of atherosclerotic plaques populated by macrophages, whereas a low level of fluorescence was detected uniformly dispersed across the lesion. The uptake of the folate conjugate by U937 macrophage cells grown in a high-lipid culture medium was significantly higher than in controls. Our data thus indicate that hyperlipidemic conditions induce an increased uptake of folate attributable to the over-expression of FRs on activated macrophages. This increase in FR expression can be exploited to deliver folate-linked compounds selectively to atherosclerotic lesions.
Antohe
Felicia
F
Institute of Cellular Biology and Pathology N. Simionescu, Bucharest, Romania. felicia.antohe@icbp.ro
Radulescu
Luminita
L
Puchianu
Elena
E
Kennedy
Michael D
MD
Low
Philip S
PS
Simionescu
Maya
M
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D006224:Cricetinae; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D011956:Receptors, Cell Surface / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D020298:U937 Cells; D014966:Xanthenes
D002352:Carrier Proteins; D005456:Fluorescent Dyes; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D014966:Xanthenes; C034657:Texas red; D005492:Folic Acid; D016650:Fluorescein-5-isothiocyanate