Endotoxin induces fibrosis in vascular endothelial cells through a mechanism dependent on transient receptor protein melastatin 7 activity.
Endotoxin induces fibrosis in vascular endothelial cells through a mechanism dependent on transient receptor protein melastatin 7 activity.
复制标题
DOI：
10.1371/journal.pone.0094146
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Simon F
中科院分区：
文献类型：
--
作者：
Echeverría C;Montorfano I;Hermosilla T;Armisén R;Velásquez LA;Cabello-Verrugio C;Varela D;Simon F
全身性炎症性疾病，包括内毒素血症脓毒症综合征，其发病机制以内皮功能障碍为特征。已有研究表明，内毒素可通过内皮细胞向间质转化的机制诱导内皮细胞转化为活化的成纤维细胞。纤维化的发生高度依赖于细胞内钙离子浓度通过钙通道的参与而升高。然而，在内毒素诱导的内皮纤维化过程中，介导钙离子内流的钙通道的具体分子特性仍不清楚。瞬时受体潜能Melastatin 7(TRPM7)是一种钙通道，表达于多种细胞类型，包括内皮细胞。TRPM7参与了许多重要的过程，如成纤维细胞向激活的成纤维细胞或肌成纤维细胞的转化，负责这些细胞的一些特征的形成。然而，TRPM7离子通道在内毒素诱导的内皮纤维化中的作用尚不清楚。因此，我们的目的是研究TRPM7钙通道是否参与内毒素诱导的内皮纤维化。利用原代培养的内皮细胞，我们证明了TRPM7是参与内毒素诱导的内皮纤维化的关键蛋白。抑制TRPM7的表达可保护内皮细胞免受内毒素刺激的纤维化过程。下调TRPM7可阻止内毒素诱导的内皮细胞内皮细胞标志物的减少和纤维化基因的增加。此外，TRPM7的下调取消了内毒素诱导的内皮细胞ECM蛋白的增加。此外，我们还发现在内毒素刺激下，细胞内钙离子水平显著升高，其机制依赖于TRPM7的表达。这些结果表明，TRPM7是内毒素诱导的内皮纤维化机制中的一个关键蛋白。
The pathogenesis of systemic inflammatory diseases, including endotoxemia-derived sepsis syndrome, is characterized by endothelial dysfunction. It has been demonstrated that the endotoxin lipopolysaccharide (LPS) induces the conversion of endothelial cells (ECs) into activated fibroblasts through endothelialtomesenchymal transition mechanism. Fibrogenesis is highly dependent on intracellular Ca2+ concentration increases through the participation of calcium channels. However, the specific molecular identity of the calcium channel that mediates the Ca2+ influx during endotoxin-induced endothelial fibrosis is still unknown. Transient receptor potential melastatin 7 (TRPM7) is a calcium channel that is expressed in many cell types, including ECs. TRPM7 is involved in a number of crucial processes such as the conversion of fibroblasts into activated fibroblasts, or myofibroblasts, being responsible for the development of several characteristics of them. However, the role of the TRPM7 ion channel in endotoxin-induced endothelial fibrosis is unknown. Thus, our aim was to study whether the TRPM7 calcium channel participates in endotoxin-induced endothelial fibrosis. Using primary cultures of ECs, we demonstrated that TRPM7 is a crucial protein involved in endotoxin-induced endothelial fibrosis. Suppression of TRPM7 expression protected ECs from the fibrogenic process stimulated by endotoxin. Downregulation of TRPM7 prevented the endotoxin-induced endothelial markers decrease and fibrotic genes increase in ECs. In addition, TRPM7 downregulation abolished the endotoxin-induced increase in ECM proteins in ECs. Furthermore, we showed that intracellular Ca2+ levels were greatly increased upon LPS challenge in a mechanism dependent on TRPM7 expression. These results demonstrate that TRPM7 is a key protein involved in the mechanism underlying endotoxin-induced endothelial fibrosis.
登录
查看更多内容
影响因子：
10.8
作者：
Becerra, Alvaro;Echeverria, Cesar;Simon, Felipe
通讯作者：
Simon, Felipe
DOI：
10.1016/0922-3371(90)90060-a
发表时间：
1990-12-01
期刊：
CELL DIFFERENTIATION AND DEVELOPMENT
影响因子：
--
作者：
HOOK, M;MCGAVIN, MJ;SIGNAS, C
通讯作者：
SIGNAS, C
影响因子：
56.9
作者：
Launay, P;Cheng, H;Kinet, JP
通讯作者：
Kinet, JP
影响因子：
3.1
作者：
Huet, Olivier;Dupic, Laurent;Duranteau, Jacques
通讯作者：
Duranteau, Jacques
影响因子：
20.1
作者：
Du J;Xie J;Zhang Z;Tsujikawa H;Fusco D;Silverman D;Liang B;Yue L
通讯作者：
Yue L