Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity

心脏毒性 干扰素基因刺激剂 药理学 内部收益率3 阿霉素 NAD+激酶 生物 医学 细胞生物学 化学 生物化学 内科学 胞浆 转录因子 毒性 航空航天工程 工程类 化疗 基因
作者
Wei Luo,Xiaoyi Zou,Yidan Wang,Zheng Dong,Xinyu Weng,Zhiqiang Pei,Shuai Song,Yongchao Zhao,Zilun Wei,Rifeng Gao,Beijian Zhang,Liwei Liu,Peiyuan Bai,Jin Liu,Xiang Wang,Tingwen Gao,Yang Zhang,Xiaolei Sun,Hang Chen,Kai Hu,Shisuo Du,Aijun Sun,Junbo Ge
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:132 (11) 被引量:39
标识
DOI:10.1161/circresaha.122.321587
摘要

Background: Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING (stimulator of interferon genes) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC). Methods: Mice were treated with low-dose doxorubicin to induce chronic DIC. The role of the cGAS-STING pathway in DIC was evaluated in cGAS -deficiency (c GAS −/− ), Sting -deficiency ( Sting −/− ), and interferon regulatory factor 3 ( Irf3 )-deficiency ( Irf3 −/− ) mice. Endothelial cell (EC)-specific conditional Sting deficiency ( Sting flox/flox /Cdh5-Cre ERT ) mice were used to assess the importance of this pathway in ECs during DIC. We also examined the direct effects of the cGAS-STING pathway on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo. Results: In the chronic DIC model, we observed significant activation of the cGAS-STING pathway in cardiac ECs. Global cGAS , Sting , and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS-STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS-STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase (NADase) activity of CD38. Furthermore, the cardiac EC cGAS-STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto-NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin. Conclusions: Our findings indicate a critical role of the cardiac EC cGAS-STING pathway in DIC. The cGAS-STING pathway may represent a novel therapeutic target for preventing DIC.
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
东asdfghjkl完成签到,获得积分10
1秒前
66完成签到 ,获得积分10
3秒前
小垃圾10号完成签到,获得积分10
5秒前
CY完成签到,获得积分10
5秒前
舒心的茗完成签到,获得积分10
6秒前
章鱼完成签到,获得积分10
6秒前
FangyingTang完成签到,获得积分10
7秒前
dxdy完成签到 ,获得积分10
8秒前
沉默的小耳朵完成签到 ,获得积分10
9秒前
fls221完成签到,获得积分10
9秒前
Xccccc完成签到 ,获得积分10
16秒前
zy0411完成签到,获得积分10
17秒前
清秀迎松完成签到,获得积分10
18秒前
19秒前
22秒前
千桑客完成签到,获得积分10
22秒前
光亮的思柔完成签到,获得积分10
25秒前
skepticalsnails完成签到,获得积分10
26秒前
标致小翠完成签到,获得积分10
26秒前
Star完成签到 ,获得积分10
26秒前
情怀应助蓝枫采纳,获得10
29秒前
赫幼蓉完成签到 ,获得积分10
30秒前
Misaki完成签到,获得积分10
31秒前
Karry完成签到 ,获得积分10
36秒前
和谐曼凝完成签到 ,获得积分10
37秒前
steven完成签到 ,获得积分10
38秒前
小明完成签到,获得积分10
38秒前
222完成签到,获得积分10
38秒前
单纯的小土豆完成签到,获得积分10
40秒前
41秒前
42秒前
东方越彬发布了新的文献求助20
44秒前
47秒前
DMMM完成签到,获得积分10
48秒前
tutu完成签到,获得积分10
50秒前
脆脆应答完成签到,获得积分10
51秒前
zxj完成签到,获得积分10
56秒前
fan完成签到 ,获得积分10
58秒前
NexusExplorer应助科研通管家采纳,获得10
1分钟前
1分钟前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
Rechtsphilosophie 1000
Bayesian Models of Cognition:Reverse Engineering the Mind 888
Defense against predation 800
Very-high-order BVD Schemes Using β-variable THINC Method 568
Chen Hansheng: China’s Last Romantic Revolutionary 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3137101
求助须知:如何正确求助?哪些是违规求助? 2788086
关于积分的说明 7784523
捐赠科研通 2444109
什么是DOI,文献DOI怎么找? 1299758
科研通“疑难数据库(出版商)”最低求助积分说明 625574
版权声明 601011