Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
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DOI：
10.1172/jci37262
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发表时间：
2009-04-01
影响因子：
15.9
通讯作者：
Tabas, Ira A.
中科院分区：
文献类型：
--
作者：
Seimon, Tracie A.;Wang, Yibin;Tabas, Ira A.
内质网应激发生在晚期动脉粥样硬化病变中巨噬细胞丰富的区域，并有助于巨噬细胞凋亡和随后的斑块坏死。因此，改变内质网应激诱导的细胞凋亡的信号通路可能影响晚期动脉粥样硬化。在这里，我们将巨噬细胞p38 α MAPK缺乏的Apoe（-/-）小鼠置于西方饮食中，发现它们的巨噬细胞凋亡和斑块坏死明显增加。巨噬细胞p38 α缺陷病变也表现出胶原含量显著减少和纤维帽明显变薄，这表明这些小鼠的斑块进展加快。与我们的体内数据一致，我们发现在p38抑制的情况下，内质网应激诱导的培养小鼠原代巨噬细胞凋亡明显加速。药理抑制或基因消融p38可抑制培养巨噬细胞和动脉粥样硬化病变中Akt的活化。此外，抑制Akt可增强内质网应激诱导的巨噬细胞凋亡，而组成型活性肉豆蔻酰基化Akt的表达可阻断培养细胞中p38抑制导致的内质网应激诱导的凋亡增强。我们的研究结果表明，p38 α MAPK可能在体外抑制内质网应激诱导的巨噬细胞凋亡和体内晚期病变巨噬细胞凋亡中发挥关键作用。
ER stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress-induced apoptosis may affect advanced atherosclerosis. Here we placed Apoe(-/-) mice deficient in macrophage p38 alpha MAPK on a Western diet and found that they had a marked increase in macrophage apoptosis and plaque necrosis. The macrophage p38 alpha-deficient lesions also exhibited a significant reduction in collagen content and a marked thinning of the fibrous cap, which suggests that plaque progression was advanced in these mice. Consistent with our in vivo data, we found that ER stress-induced apoptosis in cultured primary mouse macrophages was markedly accelerated under conditions of p38 inhibition. Pharmacological inhibition or genetic ablation of p38 suppressed activation of Akt in cultured macrophages and in atherosclerotic lesions. In addition, inhibition of Akt enhanced ER stress-induced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress-induced apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38 alpha MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.