Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm.
Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm.
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平滑肌细胞铁调素在腹主动脉瘤中的保护作用。
DOI：
10.1161/atvbaha.123.319224
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发表时间：
2023-05
影响因子：
8.7
通讯作者：
Lakhal-Littleton, Samira
中科院分区：
文献类型：
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作者：
Loick, Paul;Mohammad, Goran Hamid;Cassimjee, Ismail;Chandrashekar, Anirudh;Lapolla, Pierfrancesco;Carrington, Alison;Vera-Aviles, Mayra;Handa, Ashok;Lee, Regent;Lakhal-Littleton, Samira
铁调素是一种肝源性激素，其通过抑制肠和脾中的铁输出体膜铁转运蛋白（铁吸收和再循环的相应位点）来控制全身铁稳态。铁调素还在心血管疾病的情况下异位表达。然而，异位hepcidin在潜在的病理生理学中的确切作用是未知的。在患有腹主动脉瘤（AAA）的患者中，铁调素在动脉瘤壁的平滑肌细胞（SMC）中被显著诱导，并且与LCN 2（脂质运载蛋白-2）的表达呈负相关，LCN 2是AAA病理学中涉及的蛋白质。此外，血浆铁调素水平与动脉瘤生长呈负相关，表明铁调素具有潜在的疾病修饰作用。为了探索SMC衍生的hepcidin在AAA设置中的作用，我们将AngII（血管紧张素-II）诱导的AAA模型应用于具有可诱导的SMC特异性hepcidin缺失的小鼠。为了确定SMC衍生的铁调素是否细胞自主地起作用，我们还使用了具有铁调素抗性铁转运蛋白C326 Y的诱导型SMC特异性敲入的小鼠。使用LCN 2中和抗体确定了LCN 2的参与。与对照组相比，SMC特异性铁调素缺失或铁调素抗性铁转运蛋白C326 Y敲入的小鼠具有更高的AAA表型。在这两种模型中，SMC表现出铁转运蛋白表达升高和铁潴留减少，伴随着未能抑制LCN 2，SMC中的自噬受损和更大的主动脉中性粒细胞浸润。用LCN 2中和抗体预处理恢复自噬，减少中性粒细胞浸润，并防止AAA表型升高。最后，与对照相比，SMC特异性铁调素缺失的小鼠的血浆铁调素水平始终较低，表明SMC衍生的铁调素有助于AAA中的循环池。SMC中的铁调素升高在AAA的形成中起保护作用。这些发现首次证明了铁调素在心血管疾病中的保护作用而不是有害作用。他们强调需要进一步探索铁调素在铁稳态紊乱以外的预后和治疗价值。
Hepcidin is a liver-derived hormone that controls systemic iron homeostasis, by inhibiting the iron exporter ferroportin in the gut and spleen, respective sites of iron absorption and recycling. Hepcidin is also expressed ectopically in the context of cardiovascular disease. However, the precise role of ectopic hepcidin in underlying pathophysiology is unknown. In patients with abdominal aortic aneurysm (AAA), hepcidin is markedly induced in smooth muscle cells (SMCs) of the aneurysm wall and inversely correlated with the expression of LCN2 (lipocalin-2), a protein implicated in AAA pathology. In addition, plasma hepcidin levels were inversely correlated with aneurysm growth, suggesting hepcidin has a potential disease-modifying role. To probe the role of SMC-derived hepcidin in the setting of AAA, we applied AngII (Angiotensin-II)-induced AAA model to mice harbouring an inducible, SMC-specific deletion of hepcidin. To determine whether SMC-derived hepcidin acted cell-autonomously, we also used mice harboring an inducible SMC-specific knock-in of hepcidin-resistant ferroportinC326Y. The involvement of LCN2 was established using a LCN2-neutralizing antibody. Mice with SMC-specific deletion of hepcidin or knock-in of hepcidin-resistant ferroportinC326Y had a heightened AAA phenotype compared with controls. In both models, SMCs exhibited raised ferroportin expression and reduced iron retention, accompanied by failure to suppress LCN2, impaired autophagy in SMCs, and greater aortic neutrophil infiltration. Pretreatment with LCN2-neutralizing antibody restored autophagy, reduced neutrophil infiltration, and prevented the heightened AAA phenotype. Finally, plasma hepcidin levels were consistently lower in mice with SMC-specific deletion of hepcidin than in controls, indicating that SMC-derived hepcidin contributes to the circulating pool in AAA. Hepcidin elevation in SMCs plays a protective role in the setting of AAA. These findings are the first demonstration of a protective rather than deleterious role for hepcidin in cardiovascular disease. They highlight the need to further explore the prognostic and therapeutic value of hepcidin outside disorders of iron homeostasis.
影响因子：
4.6
作者：
Portier I;Martinod K;Desender L;Vandeputte N;Deckmyn H;Vanhoorelbeke K;De Meyer SF
通讯作者：
De Meyer SF