Cystatin C deficiency promotes inflammation in angiotensin II-induced abdominal aortic aneurisms in atherosclerotic mice.
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.
Schulte
Stephanie
S
Cardiovascular Medicine, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB-730J, Boston, MA 02115, USA.
Sun
Jiusong
J
Libby
Peter
P
Macfarlane
Lindsey
L
Sun
Chongxiu
C
Lopez-Ilasaca
Marco
M
Shi
Guo-Ping
GP
Sukhova
Galina K
GK
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
D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D055316:Cystatin C; D000804:Angiotensin II
J Vasc Surg. 2004 Sep;40(3):512-8
15337882
Cell Struct Funct. 1999 Dec;24(6):465-70
10698261
J Clin Invest. 2007 Nov;117(11):3359-68
17932568
Circulation. 2005 Jul 12;112(2):232-40
16009808
Br J Surg. 2001 Nov;88(11):1472-5
11683743
Am J Pathol. 1993 Dec;143(6):1551-9
7504883
J Vasc Surg. 1996 Jan;23(1):172-81
8558735
J Vasc Surg. 1995 May;21(5):761-71; discussion 771-2
7539511
Arterioscler Thromb Vasc Biol. 2006 May;26(5):987-94
16497993
J Vasc Surg. 1992 Aug;16(2):139-47
1386635
Circulation. 2007 Apr 17;115(15):2065-75
17404153
J Immunol. 2004 Feb 15;172(4):2607-12
14764734
Circ Res. 2003 Mar 21;92(5):493-500
12600886
Expert Opin Biol Ther. 2006 Dec;6(12):1295-309
17223738
Eur J Vasc Endovasc Surg. 2001 Jan;21(1):51-6
11170878
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2855-60
17301245
Mol Pathol. 1999 Dec;52(6):332-40
10748866
Exp Mol Med. 2004 Dec 31;36(6):524-33
15665585
Biol Chem. 2004 Jun;385(6):493-504
15255181
Nature. 1988 Jun 30;333(6176):850-2
2968520
Atherosclerosis. 2006 Feb;184(2):302-11
15982660
Biochemistry. 1998 Mar 24;37(12):4071-9
9521728
Circulation. 1999 Jan 5-12;99(1):96-104
9884385
J Am Coll Surg. 1995 Oct;181(4):371-82
7551334
Circ Res. 2005 Feb 18;96(3):368-75
15653570
J Vasc Surg. 1989 Feb;9(2):297-304
2537434
J Mol Med (Berl). 2007 Oct;85(10):1077-88
17522832
Am Rev Respir Dis. 1990 Mar;141(3):698-705
2310099
J Biol Chem. 2006 Mar 3;281(9):6020-9
16365041
Am J Pathol. 2007 Mar;170(3):809-17
17322367
Circulation. 1997 Jan 7;95(1):205-12
8994438
Br J Pharmacol. 2001 Oct;134(4):865-70
11606327
Ann N Y Acad Sci. 1996 Nov 18;800:157-74
8958991
Circulation. 2007 Apr 3;115(13):1729-37
17372168
Coron Artery Dis. 1997 Oct;8(10):623-31
9457444
Ann N Y Acad Sci. 2006 Nov;1085:161-9
17182932
J Clin Invest. 1999 Nov;104(9):1191-7
10545518
J Immunol. 2000 Sep 1;165(5):2574-81
10946284
Immunology. 2008 May;124(1):76-88
18194276
Gene Ther. 2005 Jul;12(14):1109-18
15800662
J Clin Invest. 1998 Aug 1;102(3):576-83
9691094
Ann N Y Acad Sci. 1991;624:69-80
2064250
J Clin Invest. 2003 Mar;111(6):897-906
12639996
IUBMB Life. 2005 Apr-May;57(4-5):347-53
16036619
Apoptosis. 2006 Feb;11(2):143-9
16502253
Science. 1977 Oct 21;198(4314):313-4
910131
Arch Surg. 1984 Apr;119(4):405-9
6322726
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1621-6
12855482
J Clin Invest. 2000 Jun;105(11):1605-12
10841519