Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice
Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice
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DOI：
10.1073/pnas.97.13.7458
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发表时间：
2000-06-20
影响因子：
11.1
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Schönbeck, U;Sukhova, GK;Libby, P
阻断炎症通路可能为动脉粥样硬化的治疗提供新的途径。最近，我们和其他人已经暗示免疫介质二联体CD 40/CD 40 L CD 40配体（CD 40 ligand）在动脉粥样硬化形成和急性冠状动脉综合征中起重要作用，包括调节基质金属蛋白酶、促凝血活性、细胞因子等。阻断CD 40信号传导减少了高胆固醇血症小鼠动脉粥样硬化形成的起始和早期阶段。然而，CD 40信号传导的中断是否可以延缓进展甚至使已建立的病变消退仍然未知。我们在此报告，与对照组相比，在26周高胆固醇饮食方案的后半部分，抗CD 40 L抗体治疗随机分配的低密度脂蛋白受体缺陷小鼠没有消退，但确实显著减少了主动脉弓内，特别是胸主动脉和腹主动脉内已形成的动脉粥样硬化病变的进一步发展（应用大鼠IgG或盐水; 13周，持续高胆固醇饮食）。除了限制病变进展外，抗CD 40 L治疗还以被认为有利于斑块稳定性的方式改变了动脉粥样化的组成，例如，减少巨噬细胞和脂质的相对含量，以及增加平滑肌细胞和胶原的相对含量。这些数据暗示CD 40/CD 40 L不仅在动脉粥样硬化形成的初始事件中，而且在已建立的动脉粥样硬化的演变过程中作为关键介质。这项研究进一步支持了这种特异性炎症信号通路在动脉粥样硬化及其并发症中的重要性。
Interruption of inflammatory pathways may provide a novel approach to the therapy of atherosclerosis. Recently, we and others have implicated the immune mediator dyad CD40/CD40L (CD40 ligand), which is expressed on endothelial and smooth muscle cells, macrophages, and T lymphocytes within human atherosclerotic lesions, in aspects of atherogenesis and the acute coronary syndromes, including regulation of matrix metalloproteinases, procoagulant activity, cytokines, etc. In vivo, interruption of CD40 signaling reduced the initiation and early phases of atheroma formation in hypercholesterolemic mice. However, whether interruption of CD40 signaling can retard the progression or even regress established lesions remains unknown. We report here that anti-CD40L antibody treatment of randomly assigned low-density lipoprotein receptor-deficient mice during the second half of a 26-week regimen of high-cholesterol diet did not regress, but did significantly reduce further evolution of established atherosclerotic lesions within the aortic arch and particularly the thoracic and abdominal aorta, as compared with control treatment (application of rat-IgG or saline; 13 weeks, continued high-cholesterol diet). in addition to limiting lesion progression, anti-CD40L treatment changed the composition of atheroma in manners thought to favor plaque stability, e.g., reduced relative content of macrophages and lipid, as well as increased relative content of smooth muscle cells and collagen. These data implicate CD40/CD40L as crucial mediators not only in the initial events of atherogenesis but also during the evolution of established atheroma. This study lends further support to the importance of this specific inflammatory signaling pathway in atherosclerosis and its complications.