Increased uptake of folate conjugates by activated macrophages in experimental hyperlipemia

• Published in: Cell and tissue research Vol. 320; no. 2; pp. 277 - 285
• Main Authors: Antohe, Felicia, Radulescu, Luminita, Puchianu, Elena, Kennedy, Michael D, Low, Philip S, Simionescu, Maya
• Format: Journal Article
• Language: English
• Published: Germany Springer Nature B.V 01.05.2005
• Subjects: Animals; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Carrier Proteins - metabolism; Cell Culture Techniques; Cricetinae; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Folate Receptors, GPI-Anchored; Folic Acid - chemistry; Folic Acid - pharmacokinetics; Humans; Macrophage Activation; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - pathology; Macrophages, Peritoneal - ultrastructure; Male; Mesocricetus; Mice; Mice, Inbred Strains; Microscopy, Fluorescence; Receptors, Cell Surface - metabolism; Spectrometry, Fluorescence; U937 Cells; Xanthenes
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-004-1071-7

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.