Down regulation of GALNT3 contributes to endothelial cell injury via activation of p38 MAPK signaling pathway
Down regulation of GALNT3 contributes to endothelial cell injury via activation of p38 MAPK signaling pathway
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GALNT3 的下调通过激活 p38 MAPK 信号通路导致内皮细胞损伤
DOI：
10.1016/j.atherosclerosis.2015.12.019
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发表时间：
2016-02-01
期刊：
影响因子：
5.3
通讯作者：
Gu, Dongfeng
中科院分区：
文献类型：
--
作者：
Guo, Liwei;Wang, Laiyuan;Gu, Dongfeng
目的：GALNT 3基因编码多肽N-乙酰半乳糖胺转移酶3（GalNAc-T3），其是GalNAc-Ts家族的成员，在O-连接寡糖生物合成的第一步中将N-乙酰半乳糖胺转移至丝氨酸和苏氨酸残基的羟基。越来越多的证据表明GalNAc-Ts家族与冠状动脉疾病（coronary artery disease，CAD）有关。然而，GALNT 3在CAD中的作用是未知的。方法和结果：冠心病组（n = 58）GALNT 3 mRNA表达水平较对照组（n = 120）下降48.2%，冠心病组（n = 58）GALNT 3 mRNA表达水平较对照组（n = 120）下降48.2%。CAD血清处理的人脐静脉内皮细胞（HUVECs）在体外缺氧条件下GALNT 3表达也明显降低。GALNT 3基因的敲除可促进细胞凋亡，并上调基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-14（MMP-14）的表达。GALNT 3过表达可显著抑制HUVECs凋亡，下调MMP-2和MMP-14基因的表达; GALNT 3过表达可减弱缺氧诱导的HUVECs凋亡，降低MMP-2和MMP-14基因的表达。最后，细胞溶质p-p38 MAPK/p38 MAPK表达的比率随着GALNT 3敲低而显著增加，并且随着GALNT 3过表达而降低，而p38 MAPK抑制剂SB 203580阻断GALNT 3敲低的作用。CAD患者中GALNT 3的表达减少，GALNT 3的下调通过p38 MAPK激活促进细胞凋亡和上调MMP-2和MMP-14基因表达而参与内皮损伤。GALNT 3可能是未来CAD治疗干预的潜在靶点。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Objective: The GALNT3 gene encodes polypeptide N-acetylgalactosaminyl transferase 3 (GalNAc-T3), a member of the GalNAc-Ts family that transfers the N-acetylgalactosamine to the hydroxyl group of serine and threonine residue in the first step of O-linked oligosaccharide biosynthesis. Emerging evidences have linked GalNAc-Ts family to coronary artery disease (CAD). However the effect of GALNT3 in CAD is unknown. The present study investigated the function and mechanisms of GALNT3 gene in endothelial injury.Methods and results: The GALNT3 mRNA level was decreased by 48.2% in CAD patients (n = 58), compared with that of controls (n = 120). Expression of GALNT3 was also decreased in human umbilical vein endothelial cells (HUVECs) treated with CAD sera and subjected to hypoxia in vitro. Knockdown of GALNT3 promoted apoptosis and up-regulated the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-14 (MMP-14). Conversely, overexpression of GALNT3 significantly inhibited HUVECs apoptosis and down-regulated the expression of MMP-2 and MMP-14 genes, in addition, overexpression of GALNT3 attenuated hypoxia-induced apoptosis and expression of MMP-2 and MMP-14. Finally, the ratio of cytosolic p-p38 MAPK/p38 MAPK expression was significantly increased with GALNT3 knockdown and lower with GALNT3 overexpression, while the p38 MAPK inhibitor SB203580 blocked the effects of GALNT3 knockdown.Conclusions: Expression of GALNT3 was reduced in CAD patients, and down regulation of GALNT3 contributed to endothelial injury by promoting apoptosis and up-regulating the expression of MMP-2 and MMP-14 genes via p38 MAPK activation. GALNT3 may be a potential target for future therapeutic intervention for CAD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.