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内皮素-1诱导由LIMK2介导的程序性坏死性神经元死亡，且不依赖于一氧化氮合酶（NOS）的活性。

Endothelin-1 induces LIMK2-mediated programmed necrotic neuronal death independent of NOS activity.

作者信息

Ko Ah-Reum, Hyun Hye-Won, Min Su-Ji, Kim Ji-Eun, Kang Tae-Cheon

机构信息

Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea.

出版信息

Mol Brain. 2015 Oct 6;8:58. doi: 10.1186/s13041-015-0149-3.

DOI:10.1186/s13041-015-0149-3
PMID:26438559
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4595180/
Abstract

BACKGROUND

Recently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET-1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways.

RESULTS

Following SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection.

CONCLUSION

These findings suggest that ET-1 may be one of the upstream effectors for programmed neuronal necrosis through abnormal LIMK2 over-expression by ROCK1.

摘要

背景

最近，我们报道了LIM激酶2（LIMK2）参与癫痫持续状态（SE）后异常细胞周期蛋白D1表达诱导的程序性坏死性神经元死亡。LIMK2表达上调通过损害动力蛋白相关蛋白1（DRP1）介导的线粒体分裂诱导神经元坏死。然而，我们无法阐明LIMK2介导的神经元死亡的上游效应器。因此，我们研究了内皮素-1（ET-1）在LIMK2介导的神经元坏死中的作用，因为ET-1通过多种途径参与神经元死亡。

结果

SE后，海马中ET-1浓度及其mRNA显著增加，同时ETB受体表达上调。BQ788（一种ETB受体拮抗剂）有效减轻了SE诱导的神经元损伤以及LIMK2 mRNA/蛋白表达的降低。此外，BQ788减轻了SE后CA1神经元中Rho激酶1（ROCK1）表达的上调以及DRP1介导的线粒体分裂的损伤。BQ788还减轻了外源性ET-1注射诱导的神经元死亡和LIMK2表达的上调。

结论

这些发现表明，ET-1可能是通过ROCK1异常LIMK2过表达导致程序性神经元坏死的上游效应器之一。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/25162fa064f1/13041_2015_149_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/33c74f15dccb/13041_2015_149_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/e19952e6c6d1/13041_2015_149_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/c8e4c8b584c6/13041_2015_149_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/7801f952a537/13041_2015_149_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/ebe06ec2f1c0/13041_2015_149_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/bcb056e4e3c6/13041_2015_149_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/9d59f856e65f/13041_2015_149_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/25162fa064f1/13041_2015_149_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/33c74f15dccb/13041_2015_149_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/e19952e6c6d1/13041_2015_149_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/c8e4c8b584c6/13041_2015_149_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/7801f952a537/13041_2015_149_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/ebe06ec2f1c0/13041_2015_149_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/bcb056e4e3c6/13041_2015_149_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/9d59f856e65f/13041_2015_149_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ee/4595180/25162fa064f1/13041_2015_149_Fig8_HTML.jpg

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