Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase.
Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase.
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DOI：
10.1038/s41598-017-18260-7
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发表时间：
2018-01-08
影响因子：
4.6
通讯作者：
Takahashi N
中科院分区：
文献类型：
--
作者：
Oe Y;Ko M;Fushima T;Sato E;Karumanchi SA;Sato H;Sugawara J;Ito S;Takahashi N
肝功能障碍是重度先兆子痫（PE）、溶血、肝酶升高和血小板计数低（HELLP）综合征患者或接受抗血管内皮生长因子（VEGF）治疗患者的主要问题。过多的可溶性fms样酪氨酸激酶1（sFlt 1）拮抗VEGF已牵连在PE的发病机制。VEGF增加内皮型一氧化氮合酶（eNOS）的表达并激活它。eNOS多态性导致NO产生减少与PE相关。本研究的目的是阐明在eNOS基因产物缺失的情况下过量sFlt 1对肝功能的作用。我们首先使用腺病毒在eNOS −/−和eNOS +/+小鼠中过表达sFlt 1。过量的sFlt 1和缺乏eNOS协同增加肝转氨酶的血浆水平，加剧炎症细胞的浸润，升高肝中细胞因子的表达水平，并加重氧化应激和凝血异常。在过量sFlt 1存在下缺乏eNOS也诱导血小板减少症，而单独过量sFlt 1的eNOS +/+小鼠显示无或适度的肝脏表型。两者合计，过量的sFlt 1和eNOS的缺乏协同诱导肝功能障碍和血小板减少症，这表明VEGF和一氧化氮信号传导在健康和肝损伤状态下的肝细胞-内皮细胞串扰中的新作用。
Liver dysfunction is a major problem in patients with severe preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or in patients receiving anti-vascular endothelial growth factor (VEGF) therapy. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) that antagonizes VEGF has been implicated in the pathogenesis of PE. VEGF increases the expression of endothelial nitric oxide synthase (eNOS) and activates it. eNOS polymorphisms that cause reduced NO production are associated with PE. The aim of this study was to clarify the role on hepatic function by excess sFlt1 in the absence of eNOS gene product. We first overexpressed sFlt1 using adenovirus in eNOS −/− and eNOS +/+ mice. Excessive sFlt1 and lack of eNOS synergistically increased plasma levels of liver transaminases, exacerbated infiltration of inflammatory cells, elevated expression levels of cytokines in the liver, and aggravated oxidative stress and coagulation abnormalities. Lack of eNOS in the presence of excess sFlt1 also induced thrombocytopenia, whereas eNOS +/+ mice with excess sFlt1 alone showed no or modest liver phenotype. Taken together, excessive sFlt1 and lack of eNOS synergistically induce hepatic dysfunction and thrombocytopenia, suggesting a novel role for VEGF and nitric oxide signaling in hepatocyte-endothelial cross-talk in health and in liver injury states.
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DOI：
10.1161/atvbaha.113.301637
发表时间：
2013-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Foley EM;Gordts PLSM;Stanford KI;Gonzales JC;Lawrence R;Stoddard N;Esko JD
通讯作者：
Esko JD
影响因子：
7.3
作者：
Gélinas, DS;Bernatchez, PN;Sirois, MG
通讯作者：
Sirois, MG
影响因子：
3.2
作者：
Enquobahrie, DA;Williams, MA;Luthy, DA
通讯作者：
Luthy, DA
DOI：
10.1111/1471-0528.12375
发表时间：
2013-10-01
影响因子：
5.8
作者：
Gallos, I. D.;Sivakumar, K.;Vatish, M.
通讯作者：
Vatish, M.
DOI：
10.1016/j.bbrc.2016.12.108
发表时间：
2017-01-29
影响因子：
3.1
作者：
Hayashi, Sakiko;Oe, Yuji;Takahashi, Nobuyuki
通讯作者：
Takahashi, Nobuyuki