King's British Heart Foundation Centre, King's College London, London SE5 9NU, United Kingdom.
J Biol Chem. 2012 Jun 1;287(23):19341-5. doi: 10.1074/jbc.C112.350785. Epub 2012 Apr 9.
Atherosclerosis is initiated by the retention of lipoproteins on proteoglycans in the arterial intima. However, the mechanisms leading to proteoglycan accumulation and lipoprotein retention are poorly understood. In this study, we set out to investigate the role of ADAMTS-5 (a disintegrin and metalloprotease with thrombospondin motifs-5) in the vasculature. ADAMTS-5 was markedly reduced in atherosclerotic aortas of apolipoprotein E-null (apoE(-/-)) mice. The reduction of ADAMTS-5 was accompanied by accumulation of biglycan and versican, the major lipoprotein-binding proteoglycans, in atherosclerosis. ADAMTS-5 activity induced the release of ADAMTS-specific versican (DPEAAE(441)) and aggrecan ((374)ALGS) fragments as well as biglycan and link protein from the aortic wall. Fibroblast growth factor 2 (FGF-2) inhibited ADAMTS-5 expression in isolated aortic smooth muscle cells and blocked the spontaneous release of ADAMTS-generated versican and aggrecan fragments from aortic explants. In aortas of ADAMTS-5-deficient mice, DPEAAE(441) versican neoepitopes were not detectable. Instead, biglycan levels were increased, highlighting the role of ADAMTS-5 in the catabolism of vascular proteoglycans. Importantly, ADAMTS-5 proteolytic activity reduced the LDL binding ability of biglycan and released LDL from human aortic lesions. This study provides the first evidence implicating ADAMTS-5 in the regulation of proteoglycan turnover and lipoprotein retention in atherosclerosis.
动脉粥样硬化是由脂蛋白在动脉内膜的蛋白聚糖上的滞留引发的。然而，导致蛋白聚糖积累和脂蛋白滞留的机制还知之甚少。在这项研究中，我们旨在研究 ADAMTS-5（含血栓反应蛋白基序的解整合素和金属蛋白酶-5）在血管中的作用。载脂蛋白 E 基因敲除（apoE(-/-)）小鼠的动脉粥样硬化主动脉中 ADAMTS-5 明显减少。ADAMTS-5 的减少伴随着主要的脂蛋白结合蛋白聚糖 biglycan 和 versican 的积累。ADAMTS-5 活性诱导 ADAMTS 特异性 versican (DPEAAE(441)) 和 aggrecan ((374)ALGS) 片段以及 biglycan 和连接蛋白从主动脉壁释放。成纤维细胞生长因子 2 (FGF-2) 抑制分离的主动脉平滑肌细胞中 ADAMTS-5 的表达，并阻止 ADAMTS 生成的 versican 和 aggrecan 片段从主动脉外植体自发释放。在 ADAMTS-5 缺陷小鼠的主动脉中，检测不到 DPEAAE(441) versican 新表位。相反，biglycan 水平增加，突出了 ADAMTS-5 在血管蛋白聚糖代谢中的作用。重要的是，ADAMTS-5 的蛋白水解活性降低了 biglycan 的 LDL 结合能力，并从人主动脉病变中释放了 LDL。这项研究首次提供了 ADAMTS-5 在调节动脉粥样硬化中蛋白聚糖周转和脂蛋白滞留方面的证据。
