Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile-Induced Abdominal Aortic Aneurysm.
Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile-Induced Abdominal Aortic Aneurysm.
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DOI：
10.1161/hypertensionaha.117.09822
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发表时间：
2017-11
期刊：
影响因子：
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通讯作者：
Eguchi S
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作者：
Kawai T;Takayanagi T;Forrester SJ;Preston KJ;Obama T;Tsuji T;Kobayashi T;Boyer MJ;Cooper HA;Kwok HF;Hashimoto T;Scalia R;Rizzo V;Eguchi S
血管紧张素II(AngII)激活的表皮生长因子受体(EGFR)与腹主动脉瘤(AAA)的发生有关。在血管平滑肌细胞(VSMC)中，血管紧张素Ⅱ通过金属蛋白酶、去整合素和金属肽酶结构域17(ADAM17)激活EGFR。我们假设血管平滑肌细胞中缺乏ADAM17的小鼠可以防止血管紧张素Ⅱ依赖性AAA的发生。为了验证这一概念，对照组和VSMC ADAM17缺陷小鼠被用AngII和赖氨酰氧化酶抑制剂β-氨基丙腈共同处理以诱导AAA。我们发现，52.4%的对照组小鼠因主动脉破裂而无法存活。所有其他存活的对照组小鼠都发生了AAA，并显示出AAA病变中ADAM17的表达增强。相比之下，所有经AngII和β-氨基丙腈处理的VSMC ADAM17缺陷小鼠均存活，外径/内径缩小(分别为51%/28%)。VSMC ADAM17缺乏与EGFR激活、IL-6诱导、ER/氧化应激和腹主动脉基质沉积缺乏有关。然而，VSMC ADAM17缺陷小鼠和接受AngII和β-氨基丙腈治疗的对照组小鼠都出现了类似水平的高血压。用ADAM17抑制抗体治疗C57BL/6小鼠，而不用对照免疫球蛋白治疗，也可以防止AAA的发生。总之，VSMC ADAM17沉默或全身性ADAM17抑制似乎可以保护小鼠免受AAA的形成。其机制似乎涉及到抑制EGFR的激活。
Angiotensin II (AngII)-activated epidermal growth factor receptor (EGFR) has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMC), AngII activates EGFR via a metalloproteinase, a disintegrin and metallopeptidase domain 17 (ADAM17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17 deficient mice were co-treated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive due to aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17 deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of EGFR activation, interleukin-6 induction, ER/oxidative stress and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17 deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition appears to protect mice from AAA formation. The mechanism appears to involve suppression of EGFR activation.