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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DOI：
10.1101/2021.07.30.454447
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
P. Loick;G. Mohammad;I. Cassimjee;A. Chandrashekar;P. Lapolla;A. Carrington;A. Handa;R. Lee;S. Lakhal-Littleton
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作者：
P. Loick;G. Mohammad;I. Cassimjee;A. Chandrashekar;P. Lapolla;A. Carrington;A. Handa;R. Lee;S. Lakhal-Littleton
Hepcidin（HAMP）是一种主要在肝脏中产生的激素。它通过抑制肠和脾中的铁输出细胞膜铁转运蛋白（FPN）来控制全身铁稳态，肠和脾分别是铁吸收和再循环的部位。HAMP和FPN也异位存在于不参与系统性铁稳态的组织中。异位HAMP和FPN的生理功能才刚刚开始被发现。我们观察到HAMP表达显着增加平滑肌细胞（SMC）的腹主动脉瘤（AAA），无论是在患者和实验小鼠模型的AAA。目的探讨平滑肌细胞来源的HAMP在腹主动脉瘤（AAA）病理生理中的作用。方法和结果我们产生的小鼠窝藏一个可诱导的，SMC特异性缺失的hamp基因。然后，我们应用AAA的实验模型，同时诱导SMCs中hamp的缺失。我们发现，这些小鼠发展大动脉瘤，并有更大的发生率破裂和致命的夹层比小鼠完整的hamp在SMC。在携带HAMP抗性FPNC 326 Y的诱导型SMC特异性敲入的小鼠中观察到类似的表型。此外，我们观察到，脂质运载蛋白-2（LCN 2）（一种已知促进AAA的蛋白质）的表达在来自患者和SMC中具有完整hamp的小鼠的AAA组织中受到抑制，但在SMC中缺乏hamp的小鼠中没有。用LCN 2中和抗体治疗这些小鼠可保护它们免受SMC中hamp缺失的其他有害影响。结论本研究表明，动脉瘤组织内SMC衍生的HAMP的增加在AAA的情况下具有保护作用，并且这种保护作用涉及HAMP的细胞自主作用和局部LCN 2的抑制。这些发现是异位HAMP在疾病中的保护作用的第一个例子。他们扩展了对HAMP在肝脏外的多方面功能的理解。
Rationale Hepcidin (HAMP) is a hormone produced primarily in the liver. It controls systemic iron homeostasis by inhibiting the iron exporter ferroportin (FPN) in the gut and spleen, respective sites of iron absorption and recycling. HAMP and FPN are also found ectopically in tissues not involved in systemic iron homeostasis. The physiological functions of ectopic HAMP and FPN are only just beginning to be uncovered. We observed that HAMP expression is markedly increased in smooth muscle cells (SMCs) of abdominal aortic aneurysms (AAA), both in patients and in an experimental mouse model of AAA. Objective To understand the role of SMC-derived HAMP in the pathophysiology of AAA. Methods and Results We generated mice harbouring an inducible, SMC-specific deletion of the hamp gene. We then applied the experimental model of AAA and simultaneously induced deletion of hamp in SMCs. We found that these mice developed large aneurysms and had greater incidences of rupture and of fatal dissection than mice with intact hamp in SMCs. A similar phenotype was observed in mice harbouring an inducible SMC-specific knock-in of HAMP-resistant FPNC326Y. Additionally, we observed that expression of Lipocalin-2 (LCN2), a protein known to promote AAA, was suppressed in AAA tissue from patients and from mice with intact hamp in SMCs, but not in mice lacking hamp in SMCs. Treatment of these mice with a LCN2-neutralising antibody protected them from the otherwise detrimental effects of loss of hamp in SMCs. Conclusions The present study demonstrates that the rise in SMC-derived HAMP within the aneurysm tissue is protective in the setting of AAA, and that such protection involves the cell-autonomous action of HAMP, and suppression of local LCN2. These findings are the first example of a protective role for ectopic HAMP in disease. They expand understanding of the multifaceted functions of HAMP outside the liver.