Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility.
Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility.
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乐伐替尼通过恢复平滑肌细胞收缩性来阻止主动脉瘤生长。
DOI：
10.1172/jci.insight.140364
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发表时间：
2021-08-09
期刊：
影响因子：
8
通讯作者：
Maegdefessel L
中科院分区：
文献类型：
--
作者：
Busch A;Pauli J;Winski G;Bleichert S;Chernogubova E;Metschl S;Winter H;Trenner M;Wiegering A;Otto C;Fischer J;Reiser J;Werner J;Roy J;Brostjan C;Knappich C;Eckstein HH;Paloschi V;Maegdefessel L
腹主动脉瘤（Abdominal aortic aneurysm，AAA）是一种发病率和死亡率都很高的疾病，尤其是当其破裂时.本研究的基本原理是评价乐伐替尼（一种多酪氨酸激酶抑制剂）在限制实验性AAA生长（靶向血管平滑肌细胞（VSMC）和血管生成）中的再利用。我们将全身和局部乐伐替尼治疗应用于弹性蛋白酶诱导的小鼠主动脉瘤，RNA分析确定肌球蛋白重链11（Myh 11）是最失调的转录本。在2个独立的小鼠模型中，每日经口给药显著减少了动脉瘤形成。此外，应用高胆固醇血症低密度脂蛋白受体敲除（LDLR-/-）尤卡坦小型猪的大型动物动脉瘤模型，通过药物洗脱球囊（DEB）血管内输送乐伐替尼。在此，与DEB输送的对照治疗相比，单次局部血管内输送成功阻断了AAA进展。在动物组织（鼠和猪）以及AAA患者来源的细胞中观察到VSMC增殖减少和收缩表型恢复。除了增加MYH 11水平外，乐伐替尼还减少了下游ERK信号传导。因此，乐伐替尼是限制局部血管内输送后主动脉瘤扩张的一种有前景的治疗方法。酪氨酸激酶抑制剂能够积极影响与人类AAA疾病关键相关的途径，即使是在使用DEB的潜在新的局部递送中。
Abdominal aortic aneurysm (AAA) is a disease with high morbidity and mortality, especially when ruptured. The rationale of this study was to evaluate the repurposing of lenvatinib, a multi–tyrosine kinase inhibitor, in limiting experimental AAA growth targeting vascular smooth muscle cells (VSMCs) and angiogenesis. We applied systemic and local lenvatinib treatment to elastase-induced murine aortic aneurysms, and RNA profiling identified myosin heavy chain 11 (Myh11) as the most deregulated transcript. Daily oral treatment substantially reduced aneurysm formation in 2 independent mouse models. In addition, a large animal aneurysm model in hypercholesterolemic low-density lipoprotein receptor–knockout (LDLR–/–) Yucatan minipigs was applied to endovascularly deliver lenvatinib via drug-eluting balloons (DEBs). Here, a single local endovascular delivery blocked AAA progression successfully compared with a DEB-delivered control treatment. Reduced VSMC proliferation and a restored contractile phenotype were observed in animal tissues (murine and porcine), as well as AAA patient-derived cells. Apart from increasing MYH11 levels, lenvatinib reduced downstream ERK signaling. Hence, lenvatinib is a promising therapy to limit aortic aneurysm expansion upon local endovascular delivery. The tyrosine kinase inhibitor was able to positively affect pathways of key relevance to human AAA disease, even in a potentially new local delivery using DEBs.
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影响因子：
3.8
作者：
Hynecek, Robert L.;DeRubertis, Brian G.;Faries, Peter. L.
通讯作者：
Faries, Peter. L.
DOI：
10.1016/j.jvir.2018.03.002
发表时间：
2018-07-01
影响因子：
2.9
作者：
Bryce, Yolanda;Kim, Wonho;Samuels, Shaun
通讯作者：
Samuels, Shaun
影响因子：
5.4
作者：
Kurtelius, Arttu;Vantti, Nelli;Lindgren, Antti E.
通讯作者：
Lindgren, Antti E.
DOI：
10.1073/pnas.1717906115
发表时间：
2018-02-20
影响因子：
11.1
作者：
Di Gennaro A;Araújo AC;Busch A;Jin H;Wågsäter D;Vorkapic E;Caidahl K;Eriksson P;Samuelsson B;Maegdefessel L;Haeggström JZ
通讯作者：
Haeggström JZ
DOI：
10.1002/wsbm.1337
发表时间：
2016-05
期刊：
Wiley interdisciplinary reviews. Systems biology and medicine
影响因子：
--
作者：
Hodos RA;Kidd BA;Shameer K;Readhead BP;Dudley JT
通讯作者：
Dudley JT