Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification
Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification
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DOI：
10.1161/circresaha.115.308021
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发表时间：
2016-07-08
影响因子：
20.1
通讯作者：
Kong, Wei
中科院分区：
文献类型：
--
作者：
Fu, Yi;Gao, Cheng;Kong, Wei
基本原理：内膜钙化与动脉粥样硬化斑块负荷高度相关，但其潜在机制尚不清楚。我们最近报道，软骨寡聚基质蛋白（COMP）是血管细胞外基质的一种成分，是血管平滑肌细胞钙化的内源性抑制剂。目的：探讨COMP是否影响动脉粥样硬化钙化。方法和结果：与ApoE（-/-）COMP（-/-）小鼠相比，喂食普通饲料12个月的ApoE（-/-）COMP（-/-）小鼠在无名动脉中表现出更广泛的动脉粥样硬化钙化。小鼠为了研究COMP的起源导致动脉粥样硬化钙化，在ApoE-/和ApoE（-/-）COMP-/-小鼠之间进行骨髓移植。与移植ApoE（-/-）骨髓的小鼠相比，移植ApoE（-/-）COMP-/-骨髓的小鼠观察到钙化增强，表明骨髓来源的COMP可能在动脉粥样硬化钙化中起关键作用。此外，野生型和COMP-/-巨噬细胞的微阵列分析显示，COMP缺陷型巨噬细胞具有致动脉粥样硬化和成骨特性。整合素β 3蛋白在COMP-/-巨噬细胞中减弱，并且整合素β 3的过表达抑制由COMP缺陷引起的巨噬细胞表型的转变。此外，腺相关病毒2-整合素β 3感染减弱了ApoE（-/-）COMP（-/-）小鼠的动脉粥样硬化钙化。从机制上讲，COMP通过其C-末端直接结合整联蛋白β 3的β-尾结构域，并且通过β-尾结构域阻断COMP-整联蛋白β 3缔合模拟COMP缺陷诱导的巨噬细胞表型转变。与小鼠中的COMP缺陷类似，腺相关病毒2-β尾结构域的转导增强了Apoe（-/-）小鼠的动脉粥样硬化钙化。结论：这些结果表明，COMP缺陷通过整合素β 3驱动巨噬细胞向致动脉粥样硬化和成骨表型发展，从而加剧动脉粥样硬化钙化。
Rationale: Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification.Objective: To investigate whether COMP affects atherosclerotic calcification.Methods and Results: ApoE(-/-)COMP(-/-) mice fed with chow diet for 12 months manifested more extensive atherosclerotic calcification in the innominate arteries than did ApoE(-/-) mice. To investigate which origins of COMP contributed to atherosclerotic calcification, bone marrow transplantation was performed between ApoE-/and ApoE(-/-) COMP-/- mice. Enhanced calcification was observed in mice transplanted with ApoE(-/-) COMP-/- bone marrow compared with mice transplanted with ApoE(-/-) bone marrow, indicating that bone marrow-derived COMP may play a critical role in atherosclerotic calcification. Furthermore, microarray profiling of wild-type and COMP-/- macrophages revealed that COMP-deficient macrophages exerted atherogenic and osteogenic characters. Integrin beta 3 protein was attenuated in COMP-/- macrophages, and overexpression of integrin beta 3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2-integrin beta 3 infection attenuated atherosclerotic calcification in ApoE(-/-)COMP(-/-) mice. Mechanistically, COMP bound directly to beta-tail domain of integrin beta 3 via its C-terminus, and blocking of the COMP-integrin beta 3 association by beta-tail domain mimicked the COMP deficiency-induced shift in macrophage phenotypes. Similar to COMP deficiency in mice, transduction of adeno-associated virus 2-beta-tail domain enhanced atherosclerotic calcification in ApoE(-/-) mice.Conclusions: These results reveal that COMP deficiency acted via integrin beta 3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.