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神经酰胺生成介导醛固酮诱导的人脐静脉内皮细胞（HUVEC）损伤。

Ceramide Production Mediates Aldosterone-Induced Human Umbilical Vein Endothelial Cell (HUVEC) Damages.

作者信息

Zhang Yumei, Pan Yu, Bian Zhixiang, Chen Peihua, Zhu Shijian, Gu Huiyi, Guo Liping, Hu Chun

机构信息

Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.

出版信息

PLoS One. 2016 Jan 20;11(1):e0146944. doi: 10.1371/journal.pone.0146944. eCollection 2016.

DOI:10.1371/journal.pone.0146944
PMID:26788916
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4720365/
Abstract

Here, we studied the underlying mechanism of aldosterone (Aldo)-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L) inhibited human umbilical vein endothelial cells (HUVEC) survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18) production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P), an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS) inhibitor PDMP or the ceramide (C6) potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR) antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1) is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo.

摘要

在此，我们通过聚焦神经酰胺研究了醛固酮（Aldo）诱导血管内皮细胞损伤的潜在机制。我们证实，纳摩尔浓度的Aldo抑制人脐静脉内皮细胞（HUVEC）的存活，并诱导大量细胞凋亡。我们提出，神经酰胺（主要是C18）的产生可能是Aldo介导的HUVEC损伤的原因。鞘氨醇-1-磷酸（S1P），一种抗神经酰胺脂质，可减轻Aldo诱导的神经酰胺产生及随后的HUVEC损伤。另一方面，葡萄糖神经酰胺合酶（GCS）抑制剂PDMP或神经酰胺（C6）可增强Aldo诱导的HUVEC凋亡。依普利酮，一种盐皮质激素受体（MR）拮抗剂，几乎完全阻断Aldo诱导的C18神经酰胺产生及HUVEC损伤。在分子水平上，Aldo产生C18神经酰胺需要神经酰胺合酶1（CerS-1）。通过靶向短发夹RNA敲低CerS-1可抑制Aldo诱导的C18神经酰胺产生，并保护HUVEC免受Aldo损伤。相反，CerS-1过表达促进Aldo诱导的C18神经酰胺产生，并增强HUVEC损伤。总之，这些结果表明C18神经酰胺的产生介导了Aldo介导的HUVEC损伤。MR和CerS-1可能是调节Aldo产生C18神经酰胺的两个信号分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/18332a971528/pone.0146944.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/0959bc330d36/pone.0146944.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/ce460205e2b1/pone.0146944.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/cdc7d1dd2073/pone.0146944.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/920f0b448cab/pone.0146944.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/18332a971528/pone.0146944.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/0959bc330d36/pone.0146944.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/ce460205e2b1/pone.0146944.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/cdc7d1dd2073/pone.0146944.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/920f0b448cab/pone.0146944.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6728/4720365/18332a971528/pone.0146944.g005.jpg

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