title: CD55 deficiency protects against atherosclerosis in ApoE-deficient mice via C3a modulation of lipid metabolism.
abstract: Atherosclerosis, the leading cause of death in the Western world, is driven by chronic inflammation within the artery wall. Elements of the complement cascade are implicated in the pathogenesis, because complement proteins and their activation products are found in the atherosclerotic plaque. We examined the role of CD55, a membrane inhibitor of the complement component 3 (C3) convertase, which converts C3 into C3a and C3b, in atherosclerosis. CD55-deficient (CD55(-/-)) mice were crossed onto the atherosclerosis-prone apolipoprotein E (apoE)-deficient (apoE(-/-)) background. High fat-fed male apoE(-/-)/CD55(-/-) mice were strongly protected from developing atherosclerosis compared with apoE(-/-) controls. Lipid profiling showed significantly lower levels of triglycerides, nonesterified fatty acids, and cholesterol in apoE(-/-)/CD55(-/-) mice than that in controls after high-fat feeding, whereas body fat in apoE(-/-)/CD55(-/-) mice content was increased. Plasma levels of C3 fell, whereas concentrations of C3adesArg (alias acylation stimulating protein; ASP), produced by serum carboxypeptidase N-mediated desargination of C3a, increased in nonfasted high fat-fed apoE(-/-)/CD55(-/-) mice, indicating complement activation. Thus, complement dysregulation in the absence of CD55 provoked increased C3adesArg production that, in turn, caused altered lipid handling, resulting in atheroprotection and increased adiposity. Interventions that target complement activation in adipose tissue should be explored as lipid-decreasing strategies.
authors.affiliation: Complement Biology Group, Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ruth D
authors.initials: RD
authors.lastname: Lewis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Perry
authors.forename: Irina A
authors.initials: IA
authors.lastname: Guschina
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Jackson
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018958:CD55 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D015926:Complement C3a / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D018958:CD55 Antigens; D014280:Triglycerides; C044541:complement C3a, des-Arg-(77)-; D015926:Complement C3a; D002784:Cholesterol