First published February 1, 2012 - More info
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.
Matthew R. Alexander, Christopher W. Moehle, Jason L. Johnson, Zhengyu Yang, Jae K. Lee, Christopher L. Jackson, Gary K. Owens
Original citation: J. Clin. Invest. 2012;122(1):70–79. doi:10.1172/JCI43713.
Citation for this erratum: J. Clin. Invest. 2012;122(2):783. doi:10.1172/JCI62827.
During the preparation of this manuscript, errors were inadvertently introduced into the legends for Figures 1, 2, and 3. The correct sections of the legends appear below.
Figure 1: (B) Quantification of total atherosclerotic plaque area within the aortic root of Il1r1+/+Apoe–/– and Il1r1–/–Apoe–/– mice at 150-μm intervals from the aortic valve attachment site (P < 0.001 for difference between genotypes by Scheirer-Ray-Hare test). n = 13, Il1r1+/+Apoe–/–; n = 12, Il1r1–/–Apoe–/–. Data represent mean ± SEM.
Figure 2: L-1R1 deficiency reduces compensatory outward remodeling of atherosclerotic brachiocephalic arteries. (A) Movat staining of representative brachiocephalic arteries of Il1r1–/–Apoe–/– and Il1r1+/+Apoe–/– mice. Scale bars: 200 μm. (B–D) Atherosclerotic plaque area (B), vessel area within the IEL (P < 0.001 for difference between genotypes by 2-way ANOVA) (C), and lumen area (P < 0.001 for difference between genotypes by 2-way ANOVA after square root transformation) (D) at multiple locations along the brachiocephalic arteries of Il1r1–/–Apoe–/– and Il1r1+/+Apoe–/– mice. n = 14, Il1r1+/+Apoe–/–; n = 12, Il1r1–/–Apoe–/–. Data in B–D represent mean ± SEM.
Figure 3: (F–J) Quantification of (F) plaque collagen content based on picrosirius red staining, P < 0.001 for difference of genotypes by 2-way ANOVA, (G) plaque SMC coverage based on SM α-actin staining, P < 0.001 for difference of genotypes by the Scheirer-Ray-Hare test, (H) total plaque SMC content based on SM α-actin staining, P < 0.001 for difference of genotypes by the Scheirer-Ray-Hare test, (I) plaque macrophage content based on Mac2 staining, P = 0.01 for difference of genotypes by 2-way ANOVA after log transformation, and (J) the percentage of brachiocephalic arteries exhibiting intraplaque hemorrhage based on Movat and TER-119 staining, **P < 0.01 by Fisher’s exact test.
The JCI regrets the error.