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Article: SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells
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TitleSIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells
 
AuthorsZu, Y1
Liu, L1
Lee, MYK1
Xu, C1
Liang, Y1
Man, RY1
Vanhoutte, PM1
Wang, Y1
 
KeywordsAcetylation
AMPK
Endothelial senescence
LKB1
SIRT1
 
Issue Date2010
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
 
CitationCirculation Research, 2010, v. 106 n. 8, p. 1384-1393 [How to Cite?]
DOI: http://dx.doi.org/10.1161/CIRCRESAHA.109.215483
 
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.
 
ISSN0009-7330
2013 Impact Factor: 11.089
 
DOIhttp://dx.doi.org/10.1161/CIRCRESAHA.109.215483
 
ISI Accession Number IDWOS:000277165100008
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.

 
ReferencesReferences in Scopus
 
GrantsVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention
Molecular mechanisms underlying the hepato-protective functions of the fat cell-derived hormone adiponectin: potential roles of uncoupling protein 2
 
DC FieldValue
dc.contributor.authorZu, Y
 
dc.contributor.authorLiu, L
 
dc.contributor.authorLee, MYK
 
dc.contributor.authorXu, C
 
dc.contributor.authorLiang, Y
 
dc.contributor.authorMan, RY
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorWang, Y
 
dc.date.accessioned2010-09-06T08:04:01Z
 
dc.date.available2010-09-06T08:04:01Z
 
dc.date.issued2010
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationCirculation Research, 2010, v. 106 n. 8, p. 1384-1393 [How to Cite?]
DOI: http://dx.doi.org/10.1161/CIRCRESAHA.109.215483
 
dc.identifier.doihttp://dx.doi.org/10.1161/CIRCRESAHA.109.215483
 
dc.identifier.eissn1524-4571
 
dc.identifier.epage1393
 
dc.identifier.hkuros170218
 
dc.identifier.isiWOS:000277165100008
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.

 
dc.identifier.issn0009-7330
2013 Impact Factor: 11.089
 
dc.identifier.issue8
 
dc.identifier.openurl
 
dc.identifier.pmid20203304
 
dc.identifier.scopuseid_2-s2.0-77952496696
 
dc.identifier.spage1384
 
dc.identifier.urihttp://hdl.handle.net/10722/80233
 
dc.identifier.volume106
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofCirculation Research
 
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.relation.referencesReferences in Scopus
 
dc.rightsCirculation Research. Copyright © Lippincott Williams & Wilkins.
 
dc.subjectAcetylation
 
dc.subjectAMPK
 
dc.subjectEndothelial senescence
 
dc.subjectLKB1
 
dc.subjectSIRT1
 
dc.titleSIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine