亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Genetic inactivation of β-catenin is salubrious, whereas its activation is deleterious in desmoplakin cardiomyopathy

桥粒蛋白 MYH6 普氏球蛋白 连环素 癌症研究 心肌病 物候学 Wnt信号通路 内科学 生物 细胞生物学 医学 信号转导 心力衰竭 遗传学 基因 表型 MYH7 肌球蛋白轻链激酶 磷酸化
作者
Melis Olcum,Siyang Fan,Leila Rouhi,Sirisha Cheedipudi,Benjamin Cathcart,Hyun-Hwan Jeong,Zhongming Zhao,Priyatansh Gurha,Ali J. Marian
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:119 (17): 2712-2728 被引量:1
标识
DOI:10.1093/cvr/cvad137
摘要

Abstract Aims Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy. Methods and results The Dsp gene was conditionally deleted in the 2-week-old post-natal cardiac myocytes using tamoxifen-inducible MerCreMer mice (Myh6-McmTam:DspF/F). The cWNT/β-catenin pathway was markedly dysregulated in the Myh6-McmTam:DspF/F cardiac myocytes, as indicated by a concomitant increase in the expression of cWNT/β-catenin target genes, isoforms of its key co-effectors, and the inhibitors of the pathway. The β-catenin was inactivated or activated upon inducible deletion of its transcriptional or degron domain, respectively, in the Myh6-McmTam:DspF/F cardiac myocytes. Genetic inactivation of β-catenin in the Myh6-McmTam:DspF/F mice prolonged survival, improved cardiac function, reduced cardiac arrhythmias, and attenuated myocardial fibrosis, and cell death caused by apoptosis, necroptosis, and pyroptosis, i.e. PANoptosis. In contrast, activation of β-catenin had the opposite effects. The deleterious and the salubrious effects were independent of changes in the expression levels of the cWNT target genes and were associated with changes in several molecular and biological pathways, including cell death programmes. Conclusion The cWNT/β-catenin was markedly dysregulated in the cardiac myocytes in a mouse model of desmoplakin cardiomyopathy. Inactivation of β-catenin attenuated, whereas its activation aggravated the phenotype, through multiple molecular pathways, independent of the cWNT transcriptional activity. Thus, suppression but not activation of β-catenin might be beneficial in desmoplakin cardiomyopathy.
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
更新
大幅提高文件上传限制,最高150M (2024-4-1)

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
4秒前
白云朵儿发布了新的文献求助10
9秒前
11秒前
ektyz发布了新的文献求助10
14秒前
aa发布了新的文献求助30
16秒前
aa完成签到,获得积分10
43秒前
天天快乐应助Huang采纳,获得10
54秒前
1分钟前
螃蟹One完成签到 ,获得积分10
1分钟前
Huang发布了新的文献求助10
1分钟前
wait完成签到 ,获得积分10
1分钟前
暴躁的沧海完成签到 ,获得积分10
1分钟前
2分钟前
白云朵儿发布了新的文献求助10
2分钟前
2分钟前
白云朵儿发布了新的文献求助10
3分钟前
3分钟前
白云朵儿发布了新的文献求助10
3分钟前
wanwan47发布了新的文献求助30
4分钟前
4分钟前
心灵美诗霜完成签到 ,获得积分10
4分钟前
wodetaiyangLLL完成签到 ,获得积分10
5分钟前
lixuebin完成签到 ,获得积分10
5分钟前
七七发布了新的文献求助10
5分钟前
大个应助科研通管家采纳,获得10
6分钟前
白云朵儿发布了新的文献求助10
6分钟前
6分钟前
Orange应助七七采纳,获得10
6分钟前
酷波er应助guan采纳,获得10
7分钟前
CodeCraft应助wanwan47采纳,获得10
7分钟前
wanwan47完成签到,获得积分10
7分钟前
ruba发布了新的文献求助10
7分钟前
8分钟前
老弍发布了新的文献求助10
8分钟前
ruba关注了科研通微信公众号
8分钟前
8分钟前
8分钟前
白云朵儿发布了新的文献求助10
8分钟前
8分钟前
guan发布了新的文献求助10
8分钟前
高分求助中
Un calendrier babylonien des travaux, des signes et des mois: Séries iqqur îpuš 1036
Sustainable Land Management: Strategies to Cope with the Marginalisation of Agriculture 1000
Corrosion and Oxygen Control 600
Heterocyclic Stilbene and Bibenzyl Derivatives in Liverworts: Distribution, Structures, Total Synthesis and Biological Activity 500
重庆市新能源汽车产业大数据招商指南(两链两图两池两库两平台两清单两报告) 400
Division and square root. Digit-recurrence algorithms and implementations 400
行動データの計算論モデリング 強化学習モデルを例として 400
热门求助领域 (近24小时)
化学 材料科学 医学 生物 有机化学 工程类 生物化学 纳米技术 物理 内科学 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 电极 光电子学 量子力学
热门帖子
关注 科研通微信公众号,转发送积分 2545629
求助须知:如何正确求助?哪些是违规求助? 2175642
关于积分的说明 5600192
捐赠科研通 1896371
什么是DOI,文献DOI怎么找? 946248
版权声明 565371
科研通“疑难数据库(出版商)”最低求助积分说明 503557