Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?
Expansion of necrotic core and shedding of Mertk receptor in human carotid plaques: a role for oxidized polyunsaturated fatty acids?
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DOI：
10.1093/cvr/cvs301
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发表时间：
2013-01-01
影响因子：
10.8
通讯作者：
Pasini, Anna Fratta
中科院分区：
文献类型：
--
作者：
Garbin, Ulisse;Baggio, Elda;Pasini, Anna Fratta
坏死核心（NC）的扩大是导致斑块破裂的一个主要特征，它可能是巨噬细胞加速凋亡以及吞噬清除（胞葬作用）缺陷的结果。金属肽酶结构域17（Adam17）对Mer酪氨酸激酶（Mertk）胞外结构域的切割已被证明会产生一种可溶性Mertk蛋白（sMer），它可以抑制胞葬作用。在此，我们分析了Mertk和Adam17在人颈动脉斑块坏死核心周围组织（TANC）和外周（P）中的表达及定位。然后我们通过评估TANC的哪些成分诱导Adam17以及Mertk胞外结构域的相关切割，研究了坏死核心扩大的机制。我们研究了97个人颈动脉斑块。发现Mertk和Adam17在TANC中的表达高于在P中的表达（P＜0.001）。通过免疫组织化学方法，在靠近管腔的TANC区域，Mertk高于Adam17（P＜0.01），但在靠近坏死核心的区域则低得多（P＜0.01）。这部分TANC的提取物增加了巨噬细胞样THP - 1细胞中Adam17和Mertk的（mRNA）表达（P＜0.01），但它也诱导了Mertk胞外结构域的切割，在培养基中产生sMer（P＜0.01）。TANC提取物的这种作用主要是由其所含的F - 2 - 异前列腺素、羟基十八碳二烯酸和羟基四烯酸引起的。人颈动脉斑块TANC中含有的一些多不饱和脂肪酸的氧化衍生物是Adam17的强诱导剂，这反过来又导致sMer的产生，而sMer可抑制胞葬作用。
Expansion of necrotic core (NC), a major feature responsible for plaque disruption, is likely the consequence of accelerated macrophage apoptosis coupled with defective phagocytic clearance (efferocytosis). The cleavage of the extracellular domain of Mer tyrosine kinase (Mertk) by metallopeptidase domain17 (Adam17) has been shown to produce a soluble Mertk protein (sMer), which can inhibit efferocytosis. Herein, we analysed the expression and localization of Mertk and Adam17 in the tissue around the necrotic core (TANC) and in the periphery (P) of human carotid plaques. Then we studied the mechanisms of NC expansion by evaluating which components of TANC induce Adam17 and the related cleavage of the extracellular domain of Mertk.We studied 97 human carotid plaques. The expression of Mertk and Adam17 was found to be higher in TANC than in P (P 0.001). By immunohistochemistry, Mertk was higher than Adam17 in the area of TANC near to the lumen (P 0.01) but much lower in the area close to NC (P 0.01). The extract of this portion of TANC increased the expression (mRNA) of Adam17 and Mertk (P 0.01) in macrophage-like THP-1 cells but it also induced the cleavage of the extracellular domain of Mertk, generating sMer in the medium (P 0.01). This effect of TANC extract was most evoked by its content in F-2-isoprostanes, hydroxyoctadecadienoic acids, and hydroxytetraenoic acids.Some oxidized derivatives of polyunsaturated fatty acids contained in TANC of human carotid plaques are strong inducers of Adam17, which in turn leads to the generation of sMer, which can inhibit efferocytosis.