title: α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity.
abstract: α7 nicotinic acetylcholine receptor (α7nAChR) is a subtype of nAChR and has been reported to be involved in hypertension end-organ damage. In this study, we tested the role of α7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs).
  
  
  
  Expression of α7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated β-galactosidase activity, phosphorylation of H2A.X(Ser139), phosphorylation of Chk1(Ser317), reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of α7nAChR with a selective agonist PNU-282987 blocked Ang II-induced senescence in cultured VSMCs. Moreover, PNU-282987 treatment attenuated the Ang II infusion-induced VSMC senescence in wild-type but not in α7nAChR(-/-) mice. PNU-282987 reduced the Ang II-enhanced reactive oxygen species, lipid peroxidation, and the expression of NADPH oxidase 1, NADPH oxidase 4, and p22(phox) in cultured VSMCs isolated from wild-type but not in α7nAChR(-/-) mice. Furthermore, PNU-282987 diminished Ang II-induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16(INK4a). Finally, although α7nAChR activation by PNU-282987 did not affect the Ang II-induced downregulation of sirtuin 1 (SIRT1), it significantly increased intracellular NAD(+) levels, and thereby enhanced SIRT1 activity in an AMP-dependent protein kinase-independent manner. Depletion of SIRT1 by knockdown or SIRT1 inhibitor EX527 abrogated the antisenescence effect of α7nAChR against Ang II.
  
  
  
  Our results demonstrate that activation of α7nAChR alleviates Ang II-induced VSMC senescence through promoting NAD(+)-SIRT1 pathway, suggesting that α7nAChR may be a potential therapeutic target for the treatment of Ang II-associated vascular aging disorders.
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.).
authors.forename: Dong-Jie
authors.initials: DJ
authors.lastname: Li
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.).
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.).
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.).
authors.forename: Hui
authors.initials: H
authors.lastname: Fu
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.).
authors.forename: Liang-Sheng
authors.initials: LS
authors.lastname: Zhang
authors.affiliation: From the Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China (D.-J.L., F.H., M.N., H.F., F.-M.S.); and Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China (L.-S.Z.). fumingshen@tongji.edu.cn.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Shen
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004195:Disease Models, Animal; D005838:Genotype; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D056572:Histone Deacetylase Inhibitors; D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009243:NAD; D000804:Angiotensin II; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: angiotensin II; hypertension; lipid peroxidation; mice; reactive oxygen species