Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice
Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice
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DOI：
10.1172/jci43713
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发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
Owens, Gary K.
中科院分区：
文献类型：
--
作者：
Alexander, Matthew R.;Moehle, Christopher W.;Owens, Gary K.
动脉粥样硬化的临床并发症主要是由于动脉粥样硬化斑块生长引起的管腔阻塞，不充分的向外血管重塑和斑块不稳定导致破裂。IL-1是一种促炎细胞因子，在动物模型中促进动脉粥样硬化形成，但其在斑块不稳定和外向血管重塑中的作用尚不清楚。本文所述的研究表明，与Il 1 r1（+/+）Apoe（-/-）小鼠相比，缺乏IL-1受体I型和载脂蛋白E的小鼠（Il 1 r1（-/-）Apoe（-/-）小鼠）中的晚期动脉粥样硬化斑块意外地表现出斑块不稳定性的多种特征。这些特征包括减少斑块SMC含量和覆盖，减少斑块胶原含量，增加斑块内出血。此外，Il 1 r1（-/-）Apoe（-/-）小鼠的头臂动脉斑块大小无差异，但相对于对照组，血管面积和管腔大小减少，表明外向血管重塑减少。有趣的是，与对照组相比，Il 1 r1（-/-）Apoe（-/-）小鼠斑块和血管壁中MMP 3的表达显著降低，Mmp 3（-/-）Apoe（-/-）小鼠显示出缺陷的向外血管重塑。此外，MMP 3是IL-1诱导的SMC侵袭Matrigel所必需的。综上所述，这些结果表明，IL-1信号转导在晚期动脉粥样硬化中起着令人惊讶的双重保护作用，通过促进向外血管重塑和增强斑块稳定性的特征，至少部分通过MMP 3依赖性机制。
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.