Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice

被引:212
作者
Alexander, Matthew R. [2 ]
Moehle, Christopher W. [2 ]
Johnson, Jason L. [3 ]
Yang, Zhengyu [4 ]
Lee, Jae K. [4 ]
Jackson, Christopher L. [3 ]
Owens, Gary K. [1 ,2 ]
机构
[1] Univ Virginia, Sch Med, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
[2] Univ Virginia, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA
[3] Univ Bristol, Bristol Heart Inst, Bristol, Avon, England
[4] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA
关键词
INTERLEUKIN-1 RECEPTOR ANTAGONIST; SMOOTH-MUSCLE-CELLS; ACCELERATES ATHEROSCLEROSIS; INTRAPLAQUE HEMORRHAGE; VULNERABLE PLAQUE; COLLAGEN CONTENT; BINDING-PROTEIN; KNOCKOUT MICE; MECHANISMS; ARTERY;
D O I
10.1172/JCI43713
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
100103 [病原生物学]; 100218 [急诊医学];
摘要
Clinical complications of atherosclerosis arise primarily as a result of luminal obstruction due to atherosclerotic plaque growth, with inadequate outward vessel remodeling and plaque destabilization leading to rupture. IL-1 is a proinflammatory cytokine that promotes atherogenesis in animal models, but its role in plaque destabilization and outward vessel remodeling is unclear. The studies presented herein show that advanced atherosclerotic plaques in mice lacking both IL-1 receptor type I and apolipoprotein E (Il1r1(-/-)Apoe(-/-) mice) unexpectedly exhibited multiple features of plaque instability as compared with those of Il1r1(+/+)Apoe(-/-) mice. These features included reduced plaque SMC content and coverage, reduced plaque collagen content, and increased intraplaque hemorrhage. In addition, the brachiocephalic arteries of Il1r1(-/-)Apoe(-/-) mice exhibited no difference in plaque size, but reduced vessel area and lumen size relative to controls, demonstrating a reduction in outward vessel remodeling. Interestingly, expression of MMP3 was dramatically reduced within the plaque and vessel wall of Il1r1(-/-)Apoe(-/-) mice, and Mmp3(-/-)Apoe(-/-) mice showed defective outward vessel remodeling compared with controls. In addition, MMP3 was required for IL-1-induced SMC invasion of Matrigel in vitro. Taken together, these results show that IL-1 signaling plays a surprising dual protective role in advanced atherosclerosis by promoting outward vessel remodeling and enhancing features of plaque stability, at least in part through MMP3-dependent mechanisms.
引用
收藏
页码:70 / 79
页数:10
相关论文
共 82 条
[1]
Intracellular IL-1 receptor antagonist type 1 inhibits IL-1-induced cytokine production in keratinocytes through binding to the third component of the COP9 signalosome [J].
Banda, NK ;
Guthridge, C ;
Sheppard, D ;
Cairns, KS ;
Muggli, M ;
Bech-Otschir, D ;
Dubiel, W ;
Arend, WP .
JOURNAL OF IMMUNOLOGY, 2005, 174 (06) :3608-3616
[2]
Genomic Profiling of Tumor Necrosis Factor Alpha (TNF-α) Receptor and Interleukin-1 Receptor Knockout Mice Reveals a Link between TNF-α Signaling and Increased Severity of 1918 Pandemic Influenza Virus Infection [J].
Belisle, Sarah E. ;
Tisoncik, Jennifer R. ;
Korth, Marcus J. ;
Carter, Victoria S. ;
Proll, Sean C. ;
Swayne, David E. ;
Pantin-Jackwood, Mary ;
Tumpey, Terrence M. ;
Katze, Michael G. .
JOURNAL OF VIROLOGY, 2010, 84 (24) :12576-12588
[3]
Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in ApoE knockout mice [J].
Bentzon, Jacob F. ;
Weile, Charlotte ;
Sondergaard, Claus S. ;
Hindkjaer, Johnny ;
Kassem, Moustapha ;
Falk, Erling .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2006, 26 (12) :2696-2702
[4]
Expansive remodeling is a response of the plaque-related vessel wall in aortic roots of ApoE-deficient mice - An experiment of nature [J].
Bentzon, JF ;
Pasterkamp, G ;
Falk, E .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2003, 23 (02) :257-262
[5]
Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice [J].
Bhaskar, Vinay ;
Yin, Johnny ;
Mirza, Amer M. ;
Phan, Dan ;
Vanegas, Sandra ;
Issafras, Hassan ;
Michelson, Kristen ;
Hunter, John J. ;
Kantak, Seema S. .
ATHEROSCLEROSIS, 2011, 216 (02) :313-320
[6]
Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells [J].
Bond, M ;
Chase, AJ ;
Baker, AH ;
Newby, AC .
CARDIOVASCULAR RESEARCH, 2001, 50 (03) :556-565
[7]
Morphological predictors of arterial remodeling in coronary atherosclerosis [J].
Burke, AP ;
Kolodgie, FD ;
Farb, A ;
Weber, D ;
Virmani, R .
CIRCULATION, 2002, 105 (03) :297-303
[8]
COLLAGEN TYPE-I AND TYPE-III, COLLAGEN CONTENT, GAGS AND MECHANICAL STRENGTH OF HUMAN ATHEROSCLEROTIC PLAQUE CAPS - SPAN-WISE VARIATIONS [J].
BURLEIGH, MC ;
BRIGGS, AD ;
LENDON, CL ;
DAVIES, MJ ;
BORN, GVR ;
RICHARDSON, PD .
ATHEROSCLEROSIS, 1992, 96 (01) :71-81
[9]
Interleukin-1 Regulates Multiple Atherogenic Mechanisms in Response to Fat Feeding [J].
Chamberlain, Janet ;
Francis, Sheila ;
Brookes, Zoe ;
Shaw, Gary ;
Graham, Delyth ;
Alp, Nicholas J. ;
Dower, Steven ;
Crossman, David C. .
PLOS ONE, 2009, 4 (04)
[10]
CHEEVER AW, 1994, J IMMUNOL, V153, P753