Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation
Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation
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DOI：
10.1161/atvbaha.120.314297
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发表时间：
2020-06-01
影响因子：
8.7
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
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作者：
Hiromi, Taro;Yokoyama, Utako;Ishikawa, Yoshihiro
目的：前列腺素E-2（prostaglandin E-2，PGE 2）是腹主动脉瘤（abdominal aortic aneurysm，AAA）的一个重要标志。已在人AAA中证实血管平滑肌细胞（VSMC）中前列腺素E-2受体EP 4（前列腺素E受体4）的表达增强。虽然EP 4的适度表达有助于血管稳态，但过量的EP 4在血管病理中的作用仍然不确定。我们的目的是调查是否EP 4在VSMCs过表达加剧AAA.Approach和结果：我们构建了小鼠与EP 4在SM 22 α启动子（EP 4-Tg）下的VSMCs选择性过表达。大多数EP 4-Tg小鼠在输注Ang II（血管紧张素II）后2周内死于AAA，而给予Ang II的非转基因小鼠没有明显的表型。EP 4-Tg开发了更大的AAAs比非转基因小鼠后peraortic氯化钙应用。相比之下，EP 4（fl/+）; SM 22-Cre;ApoE（-/）㈠和EP 4（fl/+）; SM 22-Cre小鼠，它们是VSMC中的EP 4杂合敲除小鼠，分别在Ang II或CaCl 2处理后很少表现出AAA。在血管紧张素II灌注的EP 4-Tg主动脉中，Ly 6C（hi）炎性单核细胞/巨噬细胞浸润和MMP-9（基质金属蛋白酶-9）活化增强。无偏分析显示，EP 4刺激正性调节VSMCs中细胞因子受体结合基因，其中IL（白细胞介素）-6上调最强烈。在EP 4-Tg和人AAA的VSMC中，EP 4刺激通过TAK 1（转化生长因子-β-活化激酶1）、NF-κ B（核因子-κ B）、JNK（c-Jun N-末端激酶）和p38引起显著的IL-6产生。IL-6的抑制阻止了Ang II诱导的EP 4-Tg中AAA的形成。此外，EP 4刺激降低弹性蛋白/胶原交联蛋白LOX（赖氨酰氧化酶）在人和小鼠VSMCs.Conclusions：失调EP 4过度表达VSMCs促进炎症单核细胞/巨噬细胞浸润和衰减弹性蛋白/胶原纤维的形成，导致AAA恶化。
Objective:Excessive prostaglandin E-2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E-2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs.Approach and Results:We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22 alpha promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4(fl/+);SM22-Cre;ApoE(-/)(-) and EP4(fl/+);SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6C(hi) inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-beta-activated kinase 1), NF-kappa B (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs.Conclusions:Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.