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学科主题: 基础医学
题名:
Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway
作者: Zhao, Liang1,2; Li, Ai Q.1,2; Zhou, Teng F.1,2; Zhang, Meng Q.1,2; Qin, Xiao M.1,2
关键词: Exendin-4 ; angiotensin II ; senescence ; NAD(P)H oxidase
刊名: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
发表日期: 2014-12-15
DOI: 10.1152/ajpcell.00151.2014
卷: 307, 期:12, 页:C1130-C1141
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Cell Biology ; Physiology
研究领域[WOS]: Cell Biology ; Physiology
关键词[WOS]: GLUCAGON-LIKE PEPTIDE-1 ; ELEVATION MYOCARDIAL-INFARCTION ; GLP-1 RECEPTOR AGONISTS ; ENDOTHELIAL-CELLS ; PREMATURE SENESCENCE ; CELLULAR SENESCENCE ; NADPH OXIDASES ; HUMAN ATHEROSCLEROSIS ; INDEPENDENT PATHWAYS ; MOLECULAR-MECHANISMS
英文摘要:

Vascular aging has been implicated in the progression of diabetes and age-related cardiovascular disorders. Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of cytoprotective actions in addition to its glucose-lowering effect. The present study was undertaken to examine whether Exendin-4, a specific ligand for the GLP-1 receptor, could prevent angiotensin (ANG) II-induced premature senescence in vascular smooth muscle cells (VSMCs) and to determine the underlying mechanism involved. Senescence-associated beta-galactosidase (SA beta-gal) assay showed that ANG II induced premature senescence of VSMCs. Pretreatment with Exendin-4 significantly attenuated ANG II-induced generation of H2O2 and the subsequent VSMC senescence. These effects were, however, reversed in the presence of exendin fragment 9-39, a GLP-1 receptor antagonist, or PKI14-22. Moreover, a marked increase in the levels of p53 and p21 induced by ANG II was blunted by the treatment with Exendin-4. Nevertheless, Exendin-4 failed to decrease ANG II-induced expression of NAD(P)H oxidase 1 (Nox1), NAD(P)H oxidase 4 (Nox4), p22(phox), or p47(phox) in VSMCs. Mechanistically, Exendin-4 blocked ANG II-induced Rac1 activation through the cAMP/PKA signaling cascade. Specifically, NSC23766, a Rac1 inhibitor, abrogated the suppressive effects of Exendin-4 on ANG II-induced premature senescence and H2O2 generation, respectively. Thus Exendin-4 confers resistance to ANG II-induced superoxide anion generation from NAD(P)H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. These findings demonstrate that GLP-1 as well as its analogs (GLP-1-related reagents) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease.

语种: 英语
所属项目编号: 30700292 ; 30971160 ; 31271493
项目资助者: National Natural Science Foundation of China
WOS记录号: WOS:000346473400008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/53768
Appears in Collections:基础医学院_心血管所_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Inst Cardiovasc Sci, Beijing 100191, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Minist Educ, Beijing 100191, Peoples R China

Recommended Citation:
Zhao, Liang,Li, Ai Q.,Zhou, Teng F.,et al. Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway[J]. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY,2014,307(12):C1130-C1141.
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