title: Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway.
abstract: 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 β-galactosidase (SA β-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.
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China; and Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China; and Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Ai Q
authors.initials: AQ
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China; and Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Teng F
authors.initials: TF
authors.lastname: Zhou
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China; and Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Meng Q
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, China; and Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China xmqin@bjmu.edu.cn.
authors.forename: Xiao M
authors.initials: XM
authors.lastname: Qin
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004789:Enzyme Activation; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006861:Hydrogen Peroxide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000975:Antioxidants; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D016159:Tumor Suppressor Protein p53; D014688:Venoms; D013481:Superoxides; D000804:Angiotensin II; D000077270:Exenatide; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: Exendin-4; NAD(P)H oxidase; angiotensin II; senescence