NADPH Oxidase Deficiency Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice
NADPH Oxidase Deficiency Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice
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DOI：
10.1161/atvbaha.114.303086
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发表时间：
2014-11-01
影响因子：
8.7
通讯作者：
Miyazaki, Akira
中科院分区：
文献类型：
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作者：
Kigawa, Yasuyoshi;Miyazaki, Takuro;Miyazaki, Akira
目的 尽管据报道烟酰胺腺嘌呤二核苷酸磷酸氧化酶 2 (NOX2) 对于吞噬细胞宿主防御至关重要，但人们发现它会通过过量产生超氧化物而加重载脂蛋白 E (Apoe) 缺失小鼠的动脉粥样硬化。因此，我们评估了 NOX2 在腹主动脉瘤 (AAA) 实验模型中的作用，并评估了 NOX2 在 AAA 中的作用机制。 方法和结果 通过输注血管紧张素 II 在低密度脂蛋白受体缺失 (Ldlr(-/-)) 小鼠中诱导 AAA。在输注血管紧张素 II 期间，这些小鼠的腹主动脉中 Nox2 表达升高，Nox2 表达增强的主要原因是富含 NOX2 的巨噬细胞被招募到 AAA 病变中。出乎意料的是，全身性Nox2缺乏促进了AAA的发展，但降低了AAA病变中活性氧的水平。 Nox2 缺陷刺激巨噬细胞向 M1 亚群转化，增强白细胞介素 (IL)-1 和基质金属蛋白酶-9/12 mRNA 的表达。施用针对 IL-1 的中和抗体可消除 Nox2 缺陷小鼠的 AAA 发育。骨髓移植实验表明，Nox2 缺陷导致的 AAA 加重是由于骨髓来源的细胞所致。来自Nox2缺失小鼠的分离的骨髓源性巨噬细胞不能产生活性氧。相比之下，腹膜和骨髓来源的巨噬细胞中的 IL-1 表达因 Nox2 缺陷而显着增强，但腹膜中性粒细胞中的 IL-1 表达却没有显着增强。 Janus激酶/信号转导子和转录信号激活剂的药理学抑制可抑制Nox2缺陷型巨噬细胞中IL-1的过量表达，而基质金属蛋白酶-9的分泌则通过核因子B信号持续刺激。结论Nox2缺陷增强了巨噬细胞对IL-1和基质金属蛋白酶-9的分泌，破坏了AAA病变中的组织重塑功能。如果 NOX2 作为 AAA 的分子靶点，这些行为是不利的。
Objective Although nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is reportedly essential for phagocyte host defenses, it has been found to aggravate atherosclerosis in apolipoprotein E (Apoe)-null mice through excess production of superoxide. We therefore assessed the role of NOX2 in an experimental model of abdominal aortic aneurysm (AAA) and assessed the mechanism of NOX2 action in AAA.Approach and Results AAA was induced in low-density lipoprotein receptor-null (Ldlr(-/-)) mice by infusing angiotensin II. Nox2 expression was elevated in the abdominal aortae of these mice during infusion of angiotensin II, with enhanced Nox2 expression mainly because of the recruitment of NOX2-enriched macrophages into AAA lesions. Unexpectedly, systemic Nox2 deficiency promoted AAA development but reduced the level of reactive oxygen species in AAA lesions. Nox2 deficiency stimulated macrophage conversion toward the M1 subset, enhancing expression of interleukin (IL)-1 and matrix metalloproteinase-9/12 mRNA. Administration of neutralizing antibody against IL-1 abolished AAA development in Nox2-deficient mice. Bone marrow transplantation experiments revealed that AAA aggravation by Nox2 deficiency is because of bone marrow-derived cells. Isolated bone marrow-derived macrophages from Nox2-null mice could not generate reactive oxygen species. In contrast, IL-1 expression in peritoneal and bone marrow-derived macrophages, but not in peritoneal neutrophils, was substantially enhanced by Nox2 deficiency. Pharmacological inhibition of Janus kinase/signal transducers and activators of transcription signaling inhibited excess IL-1 expression in Nox2-deficient macrophages, whereas matrix metalloproteinase-9 secretion was constitutively stimulated via nuclear factor-B signals.ConclusionsNox2 deficiency enhances macrophage secretion of IL-1 and matrix metalloproteinase-9, disrupting tissue-remodeling functions in AAA lesions. These actions are unfavorable if NOX2 is to serve as a molecular target for AAA.