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Metformin attenuates angiotensin II-induced TGF beta 1 expression by targeting hepatocyte nuclear factor-4-alpha
Chen, Ruifei1,2,3; Feng, Yenan1,2,3; Wu, Jimin1,2,3; Song, Yao1,2,3; Li, Hao1,2,3; Shen, Qiang1,2,3; Li, Dan1,2,3; Zhang, Jianshu1,2,3; Lu, Zhizhen1,2,3; Xiao, Han1,2,3; Zhang, Youyi1,2,3
通讯作者Xiao, Han(1) ; Zhang, Youyi(1)
刊名BRITISH JOURNAL OF PHARMACOLOGY
2018-04-01
DOI10.1111/bph.13753
175期:8页:1217-1229
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]ACTIVATED PROTEIN-KINASE ; FACTOR 4-ALPHA ; CONCISE GUIDE ; CARDIAC FIBROSIS ; PHARMACOLOGY ; TRANSCRIPTION ; PUBLICATION ; RECEPTORS ; BINDING ; HEART
英文摘要

Background and PurposeMetformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGF1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGF1 production induced by angiotensin II (AngII) and the underlying mechanisms.

Experimental ApproachWild-type and AMPK2(-/-) C57BL/6 mice were injected s.c. with metformin or saline and infused with AngII (3mgkg(-1)day(-1)) for 7days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments.

Key ResultsIn CFs, metformin inhibited AngII-induced TGF1 expression via AMPK activation. Analysis using bioinformatics predicted a potential hepatocyte nuclear factor 4 (HNF4)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4 increased TGF1 expression in CFs. HNF4 siRNA attenuated AngII-induced TGF1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4 protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4 protein levels in wild-type mice but not in AMPK2(-/-) mice. Consequently, metformin inhibited AngII-induced TGF1 production and cardiac fibrosis in wild-type mice but not in AMPK2(-/-) mice.

Conclusions and ImplicationsHNF4 mediates AngII-induced TGF1 transcription and cardiac fibrosis. Metformin inhibits AngII-induced HNF4 expression via AMPK activation, thus decreasing TGF1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4 as a new potential therapeutic target for cardiac fibrosis.

Linked ArticlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc

语种英语
WOS记录号WOS:000428313400009
通讯作者邮箱xiaohan@bjmu.edu.cn ; zhangyy@bjmu.edu.cn
第一作者单位Peking Univ, Inst Vasc Med, Hosp 3, 59 Huayuan Bei Rd, Beijing 100191, Peoples R China
通讯作者单位Peking Univ, Inst Vasc Med, Hosp 3, 59 Huayuan Bei Rd, Beijing 100191, Peoples R China
ISSN0007-1188
引用统计
被引频次:4[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/141936
专题北京大学第三临床医学院_心血管内科
北京大学基础医学院
作者单位1.Peking Univ, Inst Vasc Med, Hosp 3, 59 Huayuan Bei Rd, Beijing 100191, Peoples R China;
2.Peking Univ, Acad Adv Interdisciplinary Studies, Key Lab Cardiovasc Mol Biol & Regulatory Peptides, Key Lab Mol Cardiovasc Sci,Minist Hlth,Minist Edu, Beijing, Peoples R China;
3.Beijing Key Lab Cardiovasc Receptors Res, Beijing, Peoples R China
推荐引用方式
GB/T 7714
Chen, Ruifei,Feng, Yenan,Wu, Jimin,et al. Metformin attenuates angiotensin II-induced TGF beta 1 expression by targeting hepatocyte nuclear factor-4-alpha[J]. BRITISH JOURNAL OF PHARMACOLOGY,2018,175(8):1217-1229.
APA Chen, Ruifei.,Feng, Yenan.,Wu, Jimin.,Song, Yao.,Li, Hao.,...&Zhang, Youyi.(2018).Metformin attenuates angiotensin II-induced TGF beta 1 expression by targeting hepatocyte nuclear factor-4-alpha.BRITISH JOURNAL OF PHARMACOLOGY,175(8),1217-1229.
MLA Chen, Ruifei,et al."Metformin attenuates angiotensin II-induced TGF beta 1 expression by targeting hepatocyte nuclear factor-4-alpha".BRITISH JOURNAL OF PHARMACOLOGY 175.8(2018):1217-1229.
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