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Article: SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells

TitleSIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells
Authors
KeywordsAcetylation
AMPK
Endothelial senescence
LKB1
SIRT1
Issue Date2010
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2010, v. 106 n. 8, p. 1384-1393 How to Cite?
AbstractRationale: Endothelial senescence causes endothelial dysfunction, promotes atherogenesis and contributes to age-related vascular disorders. SIRT1 is a conserved NAD +-dependent deacetylase possessing beneficial effects against aging-related diseases, despite that the detailed functional mechanisms are largely uncharacterized. Objective: The present study is designed to evaluate the protective effects of SIRT1 on endothelial senescence and to elucidate the underlying mechanisms. Methods and Results: An in vitro senescence model was established by prolonged culture of primary endothelial cells isolated from porcine aorta. The freshly isolated "young" cells gradually underwent senescence during 1 month of repetitive passages. Both mRNA and protein expressions of SIRT1 were progressively decreased. In contrast, the protein levels of LKB1, a serine/threonine kinase and tumor suppressor, and the phosphorylation of its downstream target AMPK(Thr172) were dramatically increased in senescent cells. Overexpression of LKB1 promoted cellular senescence and retarded endothelial proliferation, which could be blocked by increasing SIRT1 levels. Knocking down of SIRT1 induced senescence and elevated the protein levels of LKB1 and phosphorylated AMPK(Thr172). Regardless of the nutritional status, hyperactivation of AMPK was able to induce endothelial senescence. SIRT1 antagonized LKB1-dependent AMPK activation through promoting the deacetylation, ubiquitination and proteasome-mediated degradation of LKB1. The survival signaling of Akt was also found to be modulated by SIRT1 and LKB1, and could cross-regulate AMPK activity. Conclusions: SIRT1 and LKB1/AMPK are the 2 key sensor systems for regulating endothelial cell survival, proliferation and senescence. The protective activities of SIRT1 may be achieved at least in part by fine tuning the acetylation/deacetylation status and stabilities of LKB1 protein. © 2010 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/80233
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID
Funding AgencyGrant Number
Seeding Funds for Basic Research of the HKU
Hong Kong Research Grant CouncilHKU 777908M
Collaborative Research FundHKU 2/07C
Area of Excellent SchemeAoE/P-10-01
Funding Information:

This work was supported by the grants from Seeding Funds for Basic Research of the HKU (Y. Wang). Hong Kong Research Grant Council grants HKU 777908M (Y. Wang), Collaborative Research Fund (HKU 2/07C) and the Area of Excellent Scheme (AoE/P-10-01) established under University Grants Committee, HKSAR.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorZu, Yen_HK
dc.contributor.authorLiu, Len_HK
dc.contributor.authorLee, MYKen_HK
dc.contributor.authorXu, Cen_HK
dc.contributor.authorLiang, Yen_HK
dc.contributor.authorMan, RYen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorWang, Yen_HK
dc.date.accessioned2010-09-06T08:04:01Z-
dc.date.available2010-09-06T08:04:01Z-
dc.date.issued2010en_HK
dc.identifier.citationCirculation Research, 2010, v. 106 n. 8, p. 1384-1393en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/80233-
dc.description.abstractRationale: Endothelial senescence causes endothelial dysfunction, promotes atherogenesis and contributes to age-related vascular disorders. SIRT1 is a conserved NAD +-dependent deacetylase possessing beneficial effects against aging-related diseases, despite that the detailed functional mechanisms are largely uncharacterized. Objective: The present study is designed to evaluate the protective effects of SIRT1 on endothelial senescence and to elucidate the underlying mechanisms. Methods and Results: An in vitro senescence model was established by prolonged culture of primary endothelial cells isolated from porcine aorta. The freshly isolated "young" cells gradually underwent senescence during 1 month of repetitive passages. Both mRNA and protein expressions of SIRT1 were progressively decreased. In contrast, the protein levels of LKB1, a serine/threonine kinase and tumor suppressor, and the phosphorylation of its downstream target AMPK(Thr172) were dramatically increased in senescent cells. Overexpression of LKB1 promoted cellular senescence and retarded endothelial proliferation, which could be blocked by increasing SIRT1 levels. Knocking down of SIRT1 induced senescence and elevated the protein levels of LKB1 and phosphorylated AMPK(Thr172). Regardless of the nutritional status, hyperactivation of AMPK was able to induce endothelial senescence. SIRT1 antagonized LKB1-dependent AMPK activation through promoting the deacetylation, ubiquitination and proteasome-mediated degradation of LKB1. The survival signaling of Akt was also found to be modulated by SIRT1 and LKB1, and could cross-regulate AMPK activity. Conclusions: SIRT1 and LKB1/AMPK are the 2 key sensor systems for regulating endothelial cell survival, proliferation and senescence. The protective activities of SIRT1 may be achieved at least in part by fine tuning the acetylation/deacetylation status and stabilities of LKB1 protein. © 2010 American Heart Association, Inc.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.orgen_HK
dc.relation.ispartofCirculation Researchen_HK
dc.rightsCirculation Research. Copyright © Lippincott Williams & Wilkins.en_HK
dc.subjectAcetylationen_HK
dc.subjectAMPKen_HK
dc.subjectEndothelial senescenceen_HK
dc.subjectLKB1en_HK
dc.subjectSIRT1en_HK
dc.titleSIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0009-7330&volume=106&spage=1384&epage=1393&date=2010&atitle=SIRT1+Promotes+Proliferation+and+Prevents+Senescence+Through+Targeting+LKB1+in+Primary+Porcine+Aortic+Endothelial+Cellsen_HK
dc.identifier.emailMan, RY: rykman@hkucc.hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.authorityMan, RY=rp00236en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/CIRCRESAHA.109.215483en_HK
dc.identifier.pmid20203304-
dc.identifier.scopuseid_2-s2.0-77952496696en_HK
dc.identifier.hkuros170218en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952496696&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1384en_HK
dc.identifier.epage1393en_HK
dc.identifier.eissn1524-4571-
dc.identifier.isiWOS:000277165100008-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention-
dc.relation.projectMolecular mechanisms underlying the hepato-protective functions of the fat cell-derived hormone adiponectin: potential roles of uncoupling protein 2-
dc.identifier.scopusauthoridZu, Y=36098466200en_HK
dc.identifier.scopusauthoridLiu, L=21737444900en_HK
dc.identifier.scopusauthoridLee, MYK=22980015700en_HK
dc.identifier.scopusauthoridXu, C=55245075900en_HK
dc.identifier.scopusauthoridLiang, Y=35305492300en_HK
dc.identifier.scopusauthoridMan, RY=7004986435en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK

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