铜转运 ATP7A（铜转运 P 型 ATP 酶/ Menkes ATP 酶）限制血管炎症和主动脉瘤的发展：微小 RNA-125b 的作用。
Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b.
机构信息
From the Vascular Biology Center (V.S., A.D., T.H., D.A., S.L., B.S., G.C., D.F., N.L.W., H.W.K., M.U.-F., T.F.), Medical College of Georgia at Augusta University, GA.
Department of Pharmacology and Toxicology (V.S., A.D., B.S., G.C., D.F., T.F.), Medical College of Georgia at Augusta University, GA.
出版信息
Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2320-2337. doi: 10.1161/ATVBAHA.119.313374. Epub 2019 Sep 26.
OBJECTIVE
Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, we show that Cu chelator markedly inhibited Ang II (angiotensin II)-induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II-induced AAA formation. Conversely, Cu transport dysfunctional ATP7A/ApoE mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1/ApoE mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7A/ApoE mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-κB negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7A/ApoE mice and reversed by locked nucleic acid-anti-miR-125b infusion.
CONCLUSIONS
ATP7A downregulation/dysfunction promotes AAA formation via upregulating miR-125b, which augments proinflammatory signaling in a Cu-dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.
目的
铜（Cu）是一种必需的微量营养素，其失调与主动脉瘤（AA）的发展有关。Cu 输出器 ATP7A（铜转运 P 型 ATP 酶/ Menkes ATP 酶）通过 Cu 伴侣 Atox1（抗氧化剂 1）将 Cu 输送给分泌型 Cu 酶，如赖氨酰氧化酶，并排除多余的 Cu。赖氨酰氧化酶被证明可以防止 AA 的形成。然而，ATP7A 在 AA 发病机制中的作用和机制尚不清楚。方法和结果：在这里，我们表明，Cu 螯合剂明显抑制了 Ang II（血管紧张素 II）诱导的腹主动脉 AA（AAA），其中 ATP7A 表达明显下调。过表达转基因 ATP7A 可防止 Ang II 诱导的 AAA 形成。相反，Cu 转运功能障碍的 ATP7A/ApoE 小鼠表现出强烈的 AAA 形成和夹层，X 射线荧光显微镜评估的主动脉 Cu 积累增加，赖氨酰氧化酶活性降低。相比之下，Atox1/ApoE 小鼠中未观察到 AAA 形成，表明赖氨酰氧化酶活性降低，这取决于 ATP7A 和 Atox1，不足以形成 AAA。骨髓移植表明，ATP7A 在 AAA 发展中对血管细胞而不是骨髓细胞很重要。微 RNA（miRNA）阵列确定 miR-125b 是来自 ATP7A/ApoE 小鼠的 AAA 中高度上调的 miRNA。此外，miR-125b 的靶基因（组蛋白甲基转移酶 Suv39h1 和 NF-κB 负调节剂 TNFAIP3[肿瘤坏死因子α诱导蛋白 3]）下调，导致促炎细胞因子表达增加、主动脉巨噬细胞募集、MMP（基质金属蛋白酶）-2/9 活性、弹性蛋白片段化和血管平滑肌细胞丢失在 ATP7A/ApoE 小鼠中，并通过锁定核酸-抗-miR-125b 输注逆转。结论：ATP7A 的下调/功能障碍通过上调 miR-125b 促进 AAA 的形成，从而以 Cu 依赖性方式增强促炎信号。因此，ATP7A 是炎症性血管疾病的潜在治疗靶点。
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