Upregulation of Endothelial DKK1 (Dickkopf 1) Promotes the Development of Pulmonary Hypertension Through the Sp1 (Specificity Protein 1)/SHMT2 (Serine Hydroxymethyltransferase 2) Pathway

丝氨酸羟甲基转移酶 丹麦克朗 生物 下调和上调 内分泌学 丝氨酸 细胞生物学 内科学 信号转导 生物化学 医学 Wnt信号通路 基因 磷酸化
作者
Qianqian Wang,Jingjing Tian,Xuan Li,Xiaolin Liu,Tengfei Zheng,Yachao Zhao,Xiao Li,Hongyu Zhong,Dongdong Liu,Wencheng Zhang,Meng Zhang,Mengmeng Li,Mei Zhang
出处
期刊:Hypertension [Lippincott Williams & Wilkins]
卷期号:79 (5): 960-973 被引量:14
标识
DOI:10.1161/hypertensionaha.121.18672
摘要

Background: Pulmonary hypertension (PH) is a cancer-like proliferative disease, which has no curative treatment options. The dysfunction of pulmonary artery endothelial cells plays a key role in PH. DKK1 (Dickkopf 1) is a secretory glycoprotein that exerts proproliferative effects on tumor cells. In the present study, we aimed to identify the role and underlying mechanism of DKK1 in the development of PH, which still remain unclear. Methods and Results: We found endothelial DKK1 expression was upregulated in serum and lung tissues obtained from patients with PH, mice with hypoxia-induced PH, and human pulmonary artery endothelial cells cultured under hypoxic conditions. Endothelium-specific DKK1-knockout (DKK1 ECKO ) mice significantly ameliorated hypoxia+Sugen5416 and hypoxia-induced PH. More importantly, neutralizing anti-DKK1 antibody treatment significantly attenuated established hypoxia+Sugen5416 PH. Results of proteome analysis of control and DKK1-knockdown human pulmonary artery endothelial cells identified a significantly differentially expressed protein, SHMT2 (serine hydroxymethyltransferase 2), a key metabolic enzyme in one-carbon metabolism, as a novel DKK1 target. DKK1 knockdown in human pulmonary artery endothelial cells cultured under hypoxic conditions decreased the cellular NADPH/NADP+ ratio, increased reactive oxygen species levels and the extent of mitochondrial DNA damage, and inhibited mitochondrial membrane hyperpolarization. In the context of this altered redox defense and mitochondrial disorder, DKK1 induced a proproliferative and antiapoptotic phenotype in endothelial cells. Furthermore, we confirmed that DKK1 regulated SHMT2 transcription through the AKT–Sp1 (specificity protein 1) signaling axis. Conclusions: Our data provide robust evidence and molecular explanations for the associations between DKK1, redox defense, mitochondrial disorders, and PH and reveal a novel target for PH treatment.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
札七发布了新的文献求助10
3秒前
FREE发布了新的文献求助10
3秒前
络luo发布了新的文献求助10
3秒前
gygy2000发布了新的文献求助10
3秒前
着急的棉花糖完成签到,获得积分10
4秒前
Zhu关注了科研通微信公众号
4秒前
4秒前
茹茹完成签到,获得积分20
5秒前
激情的一斩完成签到,获得积分10
5秒前
jenningseastera应助豆子采纳,获得50
6秒前
6秒前
7秒前
弋甫发布了新的文献求助30
7秒前
思源应助追寻梦松采纳,获得10
8秒前
8秒前
还能计划完成签到,获得积分10
8秒前
天天发布了新的文献求助10
8秒前
9秒前
10秒前
yhao发布了新的文献求助10
11秒前
斯文败类应助曾经书翠采纳,获得10
12秒前
谦谦发布了新的文献求助10
12秒前
毛豆应助知足的憨人*-*采纳,获得10
13秒前
12321234完成签到,获得积分10
13秒前
15秒前
燕子发布了新的文献求助100
15秒前
阿树不是树完成签到,获得积分20
16秒前
善学以致用应助札七采纳,获得10
18秒前
wmk发布了新的文献求助10
18秒前
xrn发布了新的文献求助10
19秒前
20秒前
20秒前
tengyi完成签到 ,获得积分10
20秒前
dopamine完成签到,获得积分10
21秒前
彩色德天完成签到 ,获得积分10
21秒前
22秒前
22秒前
jialin完成签到 ,获得积分10
22秒前
fthpzhu完成签到 ,获得积分10
22秒前
高分求助中
All the Birds of the World 4000
Production Logging: Theoretical and Interpretive Elements 3000
Les Mantodea de Guyane Insecta, Polyneoptera 2000
Homolytic deamination of amino-alcohols 1000
Machine Learning Methods in Geoscience 1000
Resilience of a Nation: A History of the Military in Rwanda 888
Massenspiele, Massenbewegungen. NS-Thingspiel, Arbeiterweibespiel und olympisches Zeremoniell 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 物理 生物化学 纳米技术 计算机科学 化学工程 内科学 复合材料 物理化学 电极 遗传学 量子力学 基因 冶金 催化作用
热门帖子
关注 科研通微信公众号,转发送积分 3728783
求助须知:如何正确求助?哪些是违规求助? 3273829
关于积分的说明 9983551
捐赠科研通 2989157
什么是DOI,文献DOI怎么找? 1640194
邀请新用户注册赠送积分活动 779103
科研通“疑难数据库(出版商)”最低求助积分说明 747961