Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis.
Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis.
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DOI：
10.1084/jem.20100370
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发表时间：
2011-02-14
期刊：
影响因子：
--
通讯作者：
Biessen EA
中科院分区：
文献类型：
--
作者：
de Jager SC;Bermúdez B;Bot I;Koenen RR;Bot M;Kavelaars A;de Waard V;Heijnen CJ;Muriana FJ;Weber C;van Berkel TJ;Kuiper J;Lee SJ;Abia R;Biessen EA
TGF-β家族成员GDF-15促进易患动脉粥样硬化的LDL r缺陷小鼠的病变形成和斑块不稳定性。生长分化因子（GDF）15是转化生长因子β（TGF-β）超家族的成员，其通过目前未知的受体在急性期反应中起作用。GDF-15血清水平升高最近被确定为急性冠状动脉综合征的危险因素。我们发现GDF-15的表达随着小鼠动脉粥样硬化疾病的进展而上调，并且主要与斑块巨噬细胞共定位。低密度脂蛋白受体−/−小鼠的造血GDF-15缺乏导致初始病变形成受损，并在后期病变中增加胶原蛋白。虽然GDF-15−/−嵌合体的病变负荷没有改变，但斑块减少了巨噬细胞浸润和坏死核心形成，所有这些特征都改善了斑块稳定性。体外研究指出，GDF-15在细胞死亡调节中具有TGFβ RII依赖性调节作用。重要的是，GDF-15−/−巨噬细胞显示CCR 2表达降低，而GDF-15以严格的CCR 2和TGFβ RII依赖性方式促进巨噬细胞趋化性，这一现象在G蛋白偶联受体激酶2+/−巨噬细胞中未观察到。总之，GDF-15缺失通过抑制CCR 2介导的趋化性和调节细胞死亡在早期和晚期动脉粥样硬化中都具有有益作用。我们的研究是第一个确定GDF-15作为CCR 2/TGFβ RII依赖性血管损伤炎症反应的急性期调节剂。
The TGF-β family member GDF-15 promotes lesion formation and plaque instability in atherosclerosis-prone LDLr-deficient mice. Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor−/− mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15−/− chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15−/− macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein–coupled receptor kinase 2+/− macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.
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影响因子：
20.1
作者：
Kempf, T;Eden, M;Wollert, KC
通讯作者：
Wollert, KC
DOI：
10.1073/pnas.95.6.2985
发表时间：
1998-03-17
影响因子：
11.1
作者：
Aragay, AM;Mellado, M;Mayor, F
通讯作者：
Mayor, F
DOI：
10.1161/01.atv.0000058431.78833.f5
发表时间：
2003-03-01
影响因子：
8.7
作者：
Guo, J;Van Eck, M;Van Berkel, TJC
通讯作者：
Van Berkel, TJC
影响因子：
5.3
作者：
Hsiao, EC;Koniaris, LG;Lee, SJ
通讯作者：
Lee, SJ
影响因子：
3.6
作者：
Schlittenhardt, D;Schober, A;Kinscherf, R
通讯作者：
Kinscherf, R