title: Progression of atherosclerosis in ApoE-deficient mice that express distinct molecular forms of TNF-alpha.
abstract: TNFalpha (TNF) critically regulates inflammation-driven atherosclerosis. Because the transmembrane (tmTNF) and soluble (sTNF) forms of TNF possess distinct immuno-modulatory properties, we hypothesized that they might differentially regulate atherosclerosis progression. Three groups of male ApoE(-/-) mice were studied: one expressing wild-type TNF (WT-TNF); one expressing exclusively a mutated non-cleavable form of TNF (KI-TNF); and one deficient in TNF (KO-TNF). Mice aged 5 weeks were fed the high-fat diet for 5 (T5) and 15 weeks (T15) or a standard chow diet for 15 weeks. At T5, in mice fed the high-fat diet, no significant differences in lesion area were observed among the three groups, either in valves or in aortas. At T15, lesion areas in valves were significantly lower in KO-TNF mice compared with those in WT-TNF mice, whereas in KI-TNF mice, they were intermediate between KO- and WT-TNF mice but not significantly different from these two groups. In aortas, lesions in KI-TNF were comparable to those of KO-TNF, both being significantly lower than those in WT-TNF. Theses differences were not linked to circulating lipids, or to macrophage, actin, and collagen contents of lesions. At T15, in mice fed the chow diet, lesion areas in valves and the aortic arch were not significantly different between the three groups. Levels of IL-6, IFNgamma, IL-10, and Foxp3 mRNAs in spleens and production of IL-6, IL-10, MCP-1, RANTES, and TNFR-2 by peritoneal macrophages at T15 of the high-fat diet showed a decrease in pro-inflammatory status, more marked in KO-TNF than in KI-TNF mice. Apoptosis was reduced only in KO-TNF mice. In conclusion, these data show that TNF effects on atherosclerosis development are detectable at stages succeeding fatty streaks and that wild-type TNF is superior to tmTNF alone in promoting atherosclerosis. TNF-dependent progression of atherosclerosis is probably linked to the differential production of pro-inflammatory mediators whether tmTNF is preponderant or essentially cleaved.
authors.affiliation: Inserm, U626, Marseille, F-13385, France.
authors.forename: M
authors.initials: M
authors.lastname: Canault
authors.forename: F
authors.initials: F
authors.lastname: Peiretti
authors.forename: M
authors.initials: M
authors.lastname: Poggi
authors.forename: C
authors.initials: C
authors.lastname: Mueller
authors.forename: F
authors.initials: F
authors.lastname: Kopp
authors.forename: B
authors.initials: B
authors.lastname: Bonardo
authors.forename: D
authors.initials: D
authors.lastname: Bastelica
authors.forename: A
authors.initials: A
authors.lastname: Nicolay
authors.forename: M-C
authors.initials: MC
authors.lastname: Alessi
authors.forename: G
authors.initials: G
authors.lastname: Nalbone
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001021:Aortic Valve / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D018450:Disease Progression; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol