Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis
Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis
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DOI：
10.1096/fj.201600669r
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发表时间：
2017-02-01
期刊：
影响因子：
4.8
通讯作者：
Torzewski, Michael
中科院分区：
文献类型：
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作者：
Cheng, Fei;Twardowski, Laura;Torzewski, Michael
第一个ATP竞争性p38 α MAPK/MAPK 14抑制剂，具有优异的体内功效和选择性，skepinone-L，现已上市。我们研究了选择性抑制p38 α MAPK/MAPK 14对酶修饰LDL（eLDL）刺激的人单核细胞的影响及其对动脉粥样硬化的意义。在不同的p38 MAPK亚型中，p38 α/MAPK 14是分离的人外周血单核细胞中主要表达和活化的亚型。此外，在人颈动脉内膜切除术标本中，eLDL与p38 α MAPK/MAPK 14阳性的巨噬细胞共定位。使用人白血病细胞系THP-1和/或原代单核细胞衍生的巨噬细胞，Skepinone-L抑制eLDL诱导的p38 MAPK途径的激活，抑制eLDL诱导的分化簇36（CD 36）和ATP结合盒，亚家族A，成员1（ABCA 1）的表达，而对泡沫细胞形成没有净效应，对eLDL触发的凋亡具有细胞和时间依赖性效应，并抑制eLDL刺激的IL-8和MIP-1 β/CCL 4（巨噬细胞炎性蛋白-1 β/趋化因子，CC基序，配体4）的分泌。通过选择性抑制剂如Skepinone-L抑制p38 MAPK通路的关键信号分子p38 α MAPK/MAPK 14，最终有助于阐明p38 MAPK信号传导的复杂网络对动脉粥样硬化形成的影响，并可能提供有希望的治疗工具来预防动脉粥样硬化中的炎症级联反应。
The first ATP-competitive p38 alpha MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38 alpha MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38 alpha/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38 alpha MAPK/MAPK14 in human carotid endarterectomy specimens. Using the human leukemia cell line THP-1 and/or primary monocyte-derived macrophages, skepinone-L inhibited eLDL-induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both cluster of differentiation 36 (CD36) and ATP-binding cassette, subfamily A, member 1 (ABCA1), without a net effect on foam cell formation, had a cell- and time-dependent effect on eLDL-triggered apoptosis, and inhibited eLDL-stimulated secretion of IL-8 and MIP-1 beta/CCL4 (macrophage inflammatory protein-1 beta/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38 alpha MAPK/MAPK14, by selective inhibitors like skepinone-L, conclusively facilitates elucidation of the impact of the complex network of p38 MAPK signaling on atherogenesis and might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis.