Vaccinia virus complement control protein diminishes formation of atherosclerotic lesions: complement is centrally involved in atherosclerotic disease.
Complement is known to be activated in atherosclerotic lesions, but the importance of this event in disease pathology is a matter of debate. Studies of rabbits fed a high-fat diet have indicated complement activation as a rate-limiting step, whereas results from genetically modified mouse strains (ApoE-/- or LDLR-/-) have failed to support this finding. To resolve whether this reflects differences between species or between genetically driven and diet-induced disease, we studied the effect of a complement inhibitor, vaccinia virus complement control protein (VCP), on C57BL/6 mice, the background strain of ApoE-/- and LDLR-/- mice. Atherosclerosis was induced by a high-fat diet, and VCP (20 mg/kg) was injected once per week after the eighth week. Fatty streak development was monitored at 15 weeks by microscopic examination of oil red-O-stained sections from the root of the aorta. VCP injections led to significant (50%) reduction of lesion size (P = 0.004). Lesions were marked by gradual accumulation of lipids and macrophages but did not develop beyond the fatty streak stage. VCP activity disappeared from serum in 4 days, and the possibility therefore exists that a higher level of protection may be achieved by more frequent injections. We conclude that the development of fatty streaks in diet-induced atherosclerotic disease can be significantly retarded by prophylactic treatment with a complement inhibitor. These results support previous findings from complement-deficient rabbits and suggest that the pathogenesis of atherosclerosis in diet-induced disease differs from that induced by major defects in lipid metabolism.
Thorbjornsdottir
Perla
P
Department of Immunology, Institute of Laboratory Medicine, Landspitali University Hospital, Hringbraut, 101 Reykjavik, Iceland.
Kolka
Ragnhildur
R
Gunnarsson
Eggert
E
Bambir
Slavko H
SH
Thorgeirsson
Gudmundur
G
Kotwal
Girish J
GJ
Arason
Gudmundur J
GJ
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D003167:Complement Activation; D003165:Complement System Proteins / Q000502:physiology*; D004041:Dietary Fats; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D014616:Vaccinia virus / Q000502:physiology*; D014764:Viral Proteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D004041:Dietary Fats; D014764:Viral Proteins; C066459:complement-control protein, Vaccinia virus; D003165:Complement System Proteins