title: Cystatin C deficiency promotes inflammation in angiotensin II-induced abdominal aortic aneurisms in atherosclerotic mice.
abstract: An imbalance between cysteinyl cathepsins and their principal endogenous inhibitor cystatin C (CystC) may favor proteolysis in the pathogenesis of human abdominal aortic aneurysms (AAA), yet a direct role of CystC in AAA remains unproven. This study used CystC and apolipoprotein E (ApoE) compound mutant (CystC(-/-)ApoE(-/-)) mice to examine directly the role of cysteine protease/protease inhibitor imbalance in AAA formation in angiotensin II-induced AAA. CystC-deficiency increased lumenal diameter and lesion size compared with control mice. CystC(-/-) ApoE(-/-) lesions also demonstrated enhanced inflammatory cell accumulation, more severe elastin fragmentation, and fewer smooth muscle cells in the tunica media. Macrophage content, measured as percent positive area (23.2 +/- 1.4% versus 11.2 +/- 1.4%; P = 0.0003) and number of the CD4(+) T cells (ninefold; P = 0.048), increased significantly in CystC(-/-)ApoE(-/-) lesions. CystC deficiency increased cathepsin activity (5.5 fold; P = 0.001) in AAA, yielding greater elastin degradation and proangiogenic laminin-5 gamma2 peptide production, which may account for increased microvascularization in CystC(-/-)ApoE(-/-) compared with ApoE(-/-) lesions. Increased leukocyte adhesion molecule VCAM-1 expression and leukocyte proliferation might also promote inflammation in CystC-deficient AAA. These data indicate that CystC contributes to experimental AAA pathogenesis and that enhanced cysteine protease activity, due to the lack of CystC, favors inflammation in AAA lesions induced in atherosclerotic mice by promoting microvascularization and smooth muscle cell apoptosis as well as leukocytes adhesion and proliferation.
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB-730J, Boston, MA 02115, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulte
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Lindsey
authors.initials: L
authors.lastname: Macfarlane
authors.forename: Chongxiu
authors.initials: C
authors.lastname: Sun
authors.forename: Marco
authors.initials: M
authors.lastname: Lopez-Ilasaca
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D055316:Cystatin C / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D055316:Cystatin C; D000804:Angiotensin II
references.citation: J Vasc Surg. 2004 Sep;40(3):512-8
references.pmid: 15337882
references.citation: Cell Struct Funct. 1999 Dec;24(6):465-70
references.pmid: 10698261
references.citation: J Clin Invest. 2007 Nov;117(11):3359-68
references.pmid: 17932568
references.citation: Circulation. 2005 Jul 12;112(2):232-40
references.pmid: 16009808
references.citation: Br J Surg. 2001 Nov;88(11):1472-5
references.pmid: 11683743
references.citation: Am J Pathol. 1993 Dec;143(6):1551-9
references.pmid: 7504883
references.citation: J Vasc Surg. 1996 Jan;23(1):172-81
references.pmid: 8558735
references.citation: J Vasc Surg. 1995 May;21(5):761-71; discussion 771-2
references.pmid: 7539511
references.citation: Arterioscler Thromb Vasc Biol. 2006 May;26(5):987-94
references.pmid: 16497993
references.citation: J Vasc Surg. 1992 Aug;16(2):139-47
references.pmid: 1386635
references.citation: Circulation. 2007 Apr 17;115(15):2065-75
references.pmid: 17404153
references.citation: J Immunol. 2004 Feb 15;172(4):2607-12
references.pmid: 14764734
references.citation: Circ Res. 2003 Mar 21;92(5):493-500
references.pmid: 12600886
references.citation: Expert Opin Biol Ther. 2006 Dec;6(12):1295-309
references.pmid: 17223738
references.citation: Eur J Vasc Endovasc Surg. 2001 Jan;21(1):51-6
references.pmid: 11170878
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2855-60
references.pmid: 17301245
references.citation: Mol Pathol. 1999 Dec;52(6):332-40
references.pmid: 10748866
references.citation: Exp Mol Med. 2004 Dec 31;36(6):524-33
references.pmid: 15665585
references.citation: Biol Chem. 2004 Jun;385(6):493-504
references.pmid: 15255181
references.citation: Nature. 1988 Jun 30;333(6176):850-2
references.pmid: 2968520
references.citation: Atherosclerosis. 2006 Feb;184(2):302-11
references.pmid: 15982660
references.citation: Biochemistry. 1998 Mar 24;37(12):4071-9
references.pmid: 9521728
references.citation: Circulation. 1999 Jan 5-12;99(1):96-104
references.pmid: 9884385
references.citation: J Am Coll Surg. 1995 Oct;181(4):371-82
references.pmid: 7551334
references.citation: Circ Res. 2005 Feb 18;96(3):368-75
references.pmid: 15653570
references.citation: J Vasc Surg. 1989 Feb;9(2):297-304
references.pmid: 2537434
references.citation: J Mol Med (Berl). 2007 Oct;85(10):1077-88
references.pmid: 17522832
references.citation: Am Rev Respir Dis. 1990 Mar;141(3):698-705
references.pmid: 2310099
references.citation: J Biol Chem. 2006 Mar 3;281(9):6020-9
references.pmid: 16365041
references.citation: Am J Pathol. 2007 Mar;170(3):809-17
references.pmid: 17322367
references.citation: Circulation. 1997 Jan 7;95(1):205-12
references.pmid: 8994438
references.citation: Br J Pharmacol. 2001 Oct;134(4):865-70
references.pmid: 11606327
references.citation: Ann N Y Acad Sci. 1996 Nov 18;800:157-74
references.pmid: 8958991
references.citation: Circulation. 2007 Apr 3;115(13):1729-37
references.pmid: 17372168
references.citation: Coron Artery Dis. 1997 Oct;8(10):623-31
references.pmid: 9457444
references.citation: Ann N Y Acad Sci. 2006 Nov;1085:161-9
references.pmid: 17182932
references.citation: J Clin Invest. 1999 Nov;104(9):1191-7
references.pmid: 10545518
references.citation: J Immunol. 2000 Sep 1;165(5):2574-81
references.pmid: 10946284
references.citation: Immunology. 2008 May;124(1):76-88
references.pmid: 18194276
references.citation: Gene Ther. 2005 Jul;12(14):1109-18
references.pmid: 15800662
references.citation: J Clin Invest. 1998 Aug 1;102(3):576-83
references.pmid: 9691094
references.citation: Ann N Y Acad Sci. 1991;624:69-80
references.pmid: 2064250
references.citation: J Clin Invest. 2003 Mar;111(6):897-906
references.pmid: 12639996
references.citation: IUBMB Life. 2005 Apr-May;57(4-5):347-53
references.pmid: 16036619
references.citation: Apoptosis. 2006 Feb;11(2):143-9
references.pmid: 16502253
references.citation: Science. 1977 Oct 21;198(4314):313-4
references.pmid: 910131
references.citation: Arch Surg. 1984 Apr;119(4):405-9
references.pmid: 6322726
references.citation: Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1621-6
references.pmid: 12855482
references.citation: J Clin Invest. 2000 Jun;105(11):1605-12
references.pmid: 10841519