ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis.
ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis.
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DOI：
10.1161/circulationaha.113.005991
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发表时间：
2014-07-08
期刊：
影响因子：
37.8
通讯作者：
Abe J
中科院分区：
文献类型：
--
作者：
Heo KS;Cushman HJ;Akaike M;Woo CH;Wang X;Qiu X;Fujiwara K;Abe J
胞吐作用是指死亡和垂死的细胞被吞噬细胞清除的过程。巨噬细胞的胞吐作用被认为可以抑制动脉粥样硬化的进展，但对这一过程的机制还缺乏深入的了解。当巨噬细胞被喂食凋亡细胞或在体外用匹伐他汀处理时，巨噬细胞凋亡相关的信号传导和吞噬能力以ERK 5活性依赖性方式上调。从巨噬细胞特异性ERK 5缺失小鼠中分离的巨噬细胞表现出减少的巨噬细胞增多和巨噬细胞增多相关分子的基因和蛋白表达水平。当这些小鼠与低密度脂蛋白受体−/−小鼠杂交并喂食高胆固醇饮食时，动脉粥样硬化斑块形成加速，斑块具有更先进和更脆弱的形态。我们的研究结果表明，ERK 5，这是强大的激活他汀类药物，是一个枢纽分子，上调巨噬细胞吞噬，从而抑制动脉粥样硬化斑块的形成。在巨噬细胞中上调ERK 5及其信号传导的分子可能是抑制心血管疾病的良好药物靶点。
Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking. When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosis-related signaling and phagocytic capacity were upregulated in an ERK5 activity–dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor−/− mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology. Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.