title: Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia.
abstract: Increased baseline values of the acute-phase reactant C-reactive protein (CRP) are significantly associated with future cardiovascular disease, and some in vitro studies have claimed that human CRP (hCRP) has proatherogenic effects. in vivo studies in apolipoprotein E-deficient mouse models, however, have given conflicting results. We bred atherosclerosis-prone mice (Apob(100/100)Ldlr(-/-)), which have human-like hypercholesterolemia, with hCRP transgenic mice (hCRP(+/0)) and studied lesion development at 15, 30, 40, and 50 weeks of age. Atherosclerotic lesions were smaller in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice than in hCRP(0/0)Apob(100/100)Ldlr(-/-) controls, as judged from the lesion surface areas of pinned-out aortas from mice at 40 and 50 weeks of age. In lesions from 40-week-old mice, mRNA expression levels of several genes in the proteasome degradation pathway were higher in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice than in littermate controls, as shown by global gene expression profiles. These results were confirmed by real-time PCR, which also indicated that the activities of those genes were the same at 30 and 40 weeks in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice but were significantly lower at 40 weeks than at 30 weeks in controls. Our results show that hCRP is not proatherogenic but instead slows atherogenesis, possibly through proteasome-mediated protein degradation.
authors: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: Alexander
authors: A
authors: Kovacs
authors: Per
authors: P
authors: Tornvall
authors: Roland
authors: R
authors: Nilsson
authors: Jesper
authors: J
authors: Tegnér
authors: Anders
authors: A
authors: Hamsten
authors: Johan
authors: J
authors: Björkegren
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D012333:RNA, Messenger; D002097:C-Reactive Protein
references: Nucleic Acids Res. 2004;32(9):e74
references: 15161944
references: Circulation. 2004 Apr 20;109(15):1870-6
references: 15037531
references: Hypertension. 2004 Jul;44(1):6-11
references: 15148294
references: J Exp Med. 1982 Jul 1;156(1):230-42
references: 7086355
references: Stain Technol. 1986 May;61(3):187-90
references: 2425463
references: Cell. 1992 Oct 16;71(2):343-53
references: 1423598
references: J Biol Chem. 1995 Jan 13;270(2):704-8
references: 7822299
references: J Exp Med. 1995 Dec 1;182(6):1959-71
references: 7500042
references: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6393-8
references: 8692825
references: J Immunol. 2004 Nov 15;173(10):6366-75
references: 15528376
references: Adv Immunol. 2005;86:241-305
references: 15705424
references: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8309-14
references: 15919817
references: Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1641-6
references: 15920030
references: Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1635-40
references: 15920036
references: Circulation. 2005 Aug 16;112(7):1016-23
references: 16087790
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2132-9
references: 16778122
references: Nat Rev Immunol. 2006 Dec;6(12):919-29
references: 17124513
references: FASEB J. 2000 Mar;14(3):532-42
references: 10698969
references: J Lipid Res. 2000 Apr;41(4):613-20
references: 10744782
references: J Clin Invest. 2000 Dec;106(12):1501-10
references: 11120757
references: Bioinformatics. 2003 Jan 22;19(2):185-93
references: 12538238
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: Circulation. 2003 Mar 11;107(9):1315-21
references: 12628954
references: Immunology. 2003 Jul;109(3):392-7
references: 12807485
references: Nat Genet. 2003 Jul;34(3):267-73
references: 12808457
references: Cardiovasc Res. 2004 Jan 1;61(1):11-21
references: 14732197
references: Circulation. 2004 Feb 10;109(5):647-55
references: 14744975
references: N Engl J Med. 2004 Apr 1;350(14):1387-97
references: 15070788
references: Circulation. 2004 Jun 15;109(23):2818-25
references: 15197153