Disruption of the Cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation
Disruption of the Cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation
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DOI：
10.1161/circulationaha.105.561449
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发表时间：
2006-01-03
期刊：
影响因子：
37.8
通讯作者：
Cleutjens, KBJM
中科院分区：
文献类型：
--
作者：
Lutgens, E;Lutgens, SPM;Cleutjens, KBJM
背景-组织蛋白酶K（catK），一种溶酶体半胱氨酸蛋白酶，在一个基因分析实验中被鉴定，该实验比较了人类早期斑块、晚期稳定斑块和含有血栓的晚期动脉粥样硬化斑块，其中在晚期稳定斑块中它被高度上调。在26周龄时，catK（-/-）/apoE（-/-）小鼠中的斑块面积减少（41.8%），这是由于晚期病变数量减少以及个体晚期斑块面积减少。这表明catK在动脉粥样硬化进展中的重要作用。catK（-/-）/apoE（-/-）小鼠的晚期斑块显示胶原含量增加。内侧弹性蛋白纤维比apoE（-/-）小鼠更不容易破裂。虽然相对巨噬细胞含量没有差异，但单个巨噬细胞大小增加。骨髓源性巨噬细胞的体外研究证实了这一观察结果。清道夫受体介导的摄取（特别是CD 36）的修饰LDL增加的情况下，catK，导致巨噬细胞的大小增加，因为增加细胞储存的胆固醇酯，从而扩大lysosome.Conclusions-A缺乏catK减少斑块的进展，诱导斑块纤维化，但在动脉粥样硬化的巨噬细胞泡沫细胞的形成。
Background-Cathepsin K (catK), a lysosomal cysteine protease, was identified in a gene-profiling experiment that compared human early plaques, advanced stable plaques, and advanced atherosclerotic plaques containing a thrombus, where it was highly upregulated in advanced stable plaques.Methods and Results-To assess the function of catK in atherosclerosis, catK(-/-)/polipoprotein (apo) E-/- mice were generated. At 26 weeks of age, plaque area in the catK(-/-)/apoE(-/-) mice was reduced (41.8%) owing to a decrease in the number of advanced lesions as well as a decrease in individual advanced plaque area. This suggests an important role for catK in atherosclerosis progression. Advanced plaques of catK(-/-)/apoE(-/-) mice showed an increase in collagen content. Medial elastin fibers were less prone to rupture than those of apoE(-/-) mice. Although the relative macrophage content did not differ, individual macrophage size increased. In vitro studies of bone marrow derived-macrophages confirmed this observation. Scavenger receptor-mediated uptake (particularly by CD36) of modified LDL increased in the absence of catK, resulting in an increased macrophage size because of increased cellular storage of cholesterol esters, thereby enlarging the lysosomes.Conclusions-A deficiency of catK reduces plaque progression and induces plaque fibrosis but aggravates macrophage foam cell formation in atherosclerosis.