Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b.
Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b.
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DOI：
10.1161/atvbaha.119.313374
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发表时间：
2019-11
期刊：
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通讯作者：
Varadarajan Sudhahar;Archita Das;Tetsuo Horimatsu;D. Ash;Silvia Leanhart;O. Antipova;S. Vogt;B. Singla;G. Csányi;Joseph White;J. Kaplan;D. Fulton;N. Weintraub;Ha Won Kim;M. Ushio-Fukai;T. Fukai
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作者：
Varadarajan Sudhahar;Archita Das;Tetsuo Horimatsu;D. Ash;Silvia Leanhart;O. Antipova;S. Vogt;B. Singla;G. Csányi;Joseph White;J. Kaplan;D. Fulton;N. Weintraub;Ha Won Kim;M. Ushio-Fukai;T. Fukai
目的：铜（Cu）是人体必需的微量营养素，其失调与主动脉瘤（AA）的发生有关。铜输出器ATP7A（铜转运p型atp酶/Menkes atp酶）通过铜伴侣Atox1（抗氧化剂1）将铜输送到分泌铜的酶，如赖氨酸氧化酶，并排除多余的铜。赖氨酸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，我们发现Cu螯合剂明显抑制Ang II（血管紧张素II）诱导的腹部AA (AAA)，其中ATP7A表达明显下调。转基因ATP7A过表达可阻止Ang ii诱导的AAA形成。相反，铜运输功能失调的ATP7Amut/+/ApoE-/-小鼠表现出强烈的AAA形成和剥离，x射线荧光显微镜检测到主动脉铜积累过多，赖氨酸氧化酶活性降低。相比之下，在Atox1-/-/ApoE-/-小鼠中未观察到AAA的形成，这表明赖氨酸氧化酶活性的降低（依赖于ATP7A和Atox1）不足以形成AAA。骨髓移植表明，在AAA的形成中，血管细胞中的ATP7A而不是骨髓细胞中的ATP7A很重要。MicroRNA （miR）阵列鉴定miR-125b是ATP7Amut/+/ApoE/小鼠AAA中高度上调的miR。此外，miR-125b靶基因（组蛋白甲基转移酶Suv39h1和NF-κ b负调节因子TNFAIP3[肿瘤坏死因子α诱导蛋白3]）下调，导致ATP7Amut/+/ApoE-/-小鼠的促炎细胞因子表达、主动脉巨噬细胞募集、MMP（基质金属蛋白酶）-2/9活性、弹性蛋白碎裂和血管平滑肌细胞损失增加，并通过锁定核酸-抗miR-125b输注逆转。结论：ATP7A下调/功能障碍通过上调miR-125b促进AAA的形成，从而以cu依赖的方式增强促炎信号。因此，ATP7A是炎症性血管疾病的潜在治疗靶点。
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 ATP7Amut/+/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 ATP7Amut/+/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 ATP7Amut/+/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.