Decorin and biglycan retain LDL in disease-prone valvular and aortic subendothelial intimal matrix.
Decorin and biglycan retain LDL in disease-prone valvular and aortic subendothelial intimal matrix.
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DOI：
10.1016/j.atherosclerosis.2013.12.038
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发表时间：
2014-03
期刊：
影响因子：
5.3
通讯作者：
Balaban, Robert S.
中科院分区：
文献类型：
--
作者：
Neufeld, Edward B.;Zadrozny, Leah M.;Phillips, Darci;Aponte, Angel;Yu, Zu-Xi;Balaban, Robert S.
内膜基质蛋白多糖对上皮下LDL的滞留是动脉粥样硬化和钙化性主动脉瓣疾病的起始步骤。在此，我们确定核心蛋白聚糖和双糖蛋白聚糖作为蛋白聚糖，优先保留在正常瓣膜和血管壁的疾病易感部位的内膜基质中的LDL。在这些研究中，分别使用来自正常非患病动物的猪主动脉瓣和肾动脉开口分流器、钙化瓣膜疾病和肾动脉粥样硬化的起始部位作为模型。荧光人LDL选择性保留在瓣膜的易病变胶原/蛋白多糖富集的主动脉表面上，此处弹性膜耗尽，如先前在肾口易病变部位观察到的。瓣膜和分流器蛋白提取物的iTRAQ质谱鉴定出核心蛋白聚糖和双糖蛋白聚糖是静电保留在人LDL亲和柱上的主要内皮下内膜基质蛋白聚糖。核心蛋白聚糖水平与两种组织中病变倾向部位的LDL结合相关。胶原蛋白与LDL的结合是蛋白多糖介导的。所有已知的基底膜蛋白聚糖结合LDL，表明它们可以调节LDL摄取到内皮下基质中。纯化的核心蛋白聚糖与人低密度脂蛋白在体外微量测定的协会被阻断血清白蛋白和肝素，这表明这些蛋白在体内的抗动脉粥样硬化作用。LDL与瓣叶和血管壁中的核心蛋白聚糖和双糖链蛋白聚糖的静电相互作用是LDL滞留的主要来源。LDL或这些蛋白聚糖上的互补静电位点可能为预防这些心血管疾病的最早期事件之一提供新的治疗靶点。
Subendothelial LDL retention by intimal matrix proteoglycans is an initial step in atherosclerosis and calcific aortic valve disease. Herein, we identify decorin and biglycan as the proteoglycans that preferentially retain LDL in intimal matrix at disease-prone sites in normal valve and vessel wall. The porcine aortic valve and renal artery ostial diverter, initiation sites of calcific valve disease and renal atherosclerosis, respectively, from normal non-diseased animals were used as models in these studies. Fluorescent human LDL was selectively retained on the lesion-prone collagen/proteoglycan-enriched aortic surface of the valve, where the elastic lamina is depleted, as previously observed in lesion-prone sites in the renal ostium. iTRAQ mass spectrometry of valve and diverter protein extracts identified decorin and biglycan as the major subendothelial intimal matrix proteoglycans electrostatically retained on human LDL affinity columns. Decorin levels correlated with LDL binding in lesion-prone sites in both tissues. Collagen binding to LDL was shown to be proteoglycan-mediated. All known basement membrane proteoglycans bound LDL suggesting they may modulate LDL uptake into the subendothelial matrix. The association of purified decorin with human LDL in an in vitro microassay was blocked by serum albumin and heparin suggesting anti-atherogenic roles for these proteins in vivo. LDL electrostatic interactions with decorin and biglycan in the valve leaflets and vascular wall is a major source of LDL retention. The complementary electrostatic sites on LDL or these proteoglycans may provide a novel therapeutic target for preventing one of the earliest events in these cardiovascular diseases.
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