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Article: Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis

TitleCyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis
Authors
Issue Date2012
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
Citation
Circulation, 2012, v. 126 n. 6 , p. 729-740 How to Cite?
Abstract
BACKGROUND: Endothelial senescence represents one of the major characteristics of vascular aging and promotes the development of atherosclerosis. Sirtuin-1 (SIRT1) is an NAD-dependent deacetylase possessing antiaging activities. During the occurrence of endothelial senescence, both the expression and activity of SIRT1 are downregulated. The present study was designed to investigate the molecular mechanisms contributing to the loss-of-SIRT1 function in senescent endothelial cells. METHODS AND RESULTS: After repetitive passages, primary cultures of porcine aortic endothelial cells exhibited a severe senescence phenotype. Western blotting revealed that phosphorylation of SIRT1 at serine 47 (S47) was significantly enhanced in senescent endothelial cells. S47 phosphorylation was stimulated by agents promoting senescence and attenuated by drugs with antisenescence properties. Mutation of S47 to nonphosphorable alanine (S47A) enhanced whereas replacing S47 with phospho-mimicking aspartic acid (S47D) abolished the antisenescent, growth-promoting, and LKB1-downregulating actions of SIRT1. Phosphorylation at S47 was critically involved in the nuclear retention of SIRT1 but abolished its association with the telomeric repeat-binding factor 2-interacting protein 1. Cyclin-dependent kinase 5 (CDK5) was identified as an SIRT1 kinase modulating S47 phosphorylation. Knockdown or inhibition of CDK5 reduced the number of senescent endothelial cells, promoted nuclear exportation of SIRT1, and attenuated the expression of inflammatory genes in porcine aortic endothelial cells. The truncated regulatory subunit of CDK5, P25, accumulated in senescent porcine aortic endothelial cells and atherosclerotic aortas. Long-term treatment with roscovitine, a CDK5 inhibitor, blocked the development of cellular senescence and atherosclerosis in aortas of hypercholesterolemic apolipoprotein E-deficient mice. CONCLUSION: CDK5-mediated hyperphosphorylation of SIRT1 facilitates the development of endothelial senescence and atherosclerosis.
DescriptionEarly Epub title: CDK5-mediated hyperphosphorylation of SIRT1 contributes to the development of endothelial senescence and atherosclerosis; Early Epub abstract link: http://circ.ahajournals.org/content/early/2012/06/29/CIRCULATIONAHA.112.118778
Persistent Identifierhttp://hdl.handle.net/10722/171450
ISSN
2013 Impact Factor: 14.948
ISI Accession Number ID
References

 

Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Chinese Academy of Sciences
DC FieldValueLanguage
dc.contributor.authorBai, Ben_US
dc.contributor.authorLiang, Yen_US
dc.contributor.authorXu, Cen_US
dc.contributor.authorLee, MYKen_US
dc.contributor.authorXu, Aen_US
dc.contributor.authorWu, Den_US
dc.contributor.authorVanhoutte, PMen_US
dc.contributor.authorWang, Yen_US
dc.date.accessioned2012-10-30T06:14:21Z-
dc.date.available2012-10-30T06:14:21Z-
dc.date.issued2012en_US
dc.identifier.citationCirculation, 2012, v. 126 n. 6 , p. 729-740en_US
dc.identifier.issn0009-7322en_US
dc.identifier.urihttp://hdl.handle.net/10722/171450-
dc.descriptionEarly Epub title: CDK5-mediated hyperphosphorylation of SIRT1 contributes to the development of endothelial senescence and atherosclerosis; Early Epub abstract link: http://circ.ahajournals.org/content/early/2012/06/29/CIRCULATIONAHA.112.118778-
dc.description.abstractBACKGROUND: Endothelial senescence represents one of the major characteristics of vascular aging and promotes the development of atherosclerosis. Sirtuin-1 (SIRT1) is an NAD-dependent deacetylase possessing antiaging activities. During the occurrence of endothelial senescence, both the expression and activity of SIRT1 are downregulated. The present study was designed to investigate the molecular mechanisms contributing to the loss-of-SIRT1 function in senescent endothelial cells. METHODS AND RESULTS: After repetitive passages, primary cultures of porcine aortic endothelial cells exhibited a severe senescence phenotype. Western blotting revealed that phosphorylation of SIRT1 at serine 47 (S47) was significantly enhanced in senescent endothelial cells. S47 phosphorylation was stimulated by agents promoting senescence and attenuated by drugs with antisenescence properties. Mutation of S47 to nonphosphorable alanine (S47A) enhanced whereas replacing S47 with phospho-mimicking aspartic acid (S47D) abolished the antisenescent, growth-promoting, and LKB1-downregulating actions of SIRT1. Phosphorylation at S47 was critically involved in the nuclear retention of SIRT1 but abolished its association with the telomeric repeat-binding factor 2-interacting protein 1. Cyclin-dependent kinase 5 (CDK5) was identified as an SIRT1 kinase modulating S47 phosphorylation. Knockdown or inhibition of CDK5 reduced the number of senescent endothelial cells, promoted nuclear exportation of SIRT1, and attenuated the expression of inflammatory genes in porcine aortic endothelial cells. The truncated regulatory subunit of CDK5, P25, accumulated in senescent porcine aortic endothelial cells and atherosclerotic aortas. Long-term treatment with roscovitine, a CDK5 inhibitor, blocked the development of cellular senescence and atherosclerosis in aortas of hypercholesterolemic apolipoprotein E-deficient mice. CONCLUSION: CDK5-mediated hyperphosphorylation of SIRT1 facilitates the development of endothelial senescence and atherosclerosis.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.orgen_US
dc.relation.ispartofCirculationen_US
dc.rightsThis is a non-final version of an article published in final form in (provide complete journal citation)-
dc.subject.meshAtherosclerosis - enzymology - pathology-
dc.subject.meshCell Aging - physiology-
dc.subject.meshCyclin-Dependent Kinase 5 - antagonists and inhibitors - physiology-
dc.subject.meshEndothelium, Vascular - enzymology - metabolism - pathology-
dc.subject.meshSirtuin 1 - genetics - metabolism-
dc.titleCyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosisen_US
dc.typeArticleen_US
dc.identifier.emailLee, MYK: leemary@hkucc.hku.hken_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hk-
dc.identifier.emailWang, Y: yuwanghk@hku.hk-
dc.identifier.authorityXu, A=rp00485en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1161/CIRCULATIONAHA.112.118778en_US
dc.identifier.pmid22753194-
dc.identifier.scopuseid_2-s2.0-84864708402en_US
dc.identifier.hkuros204677-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84864708402&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume126en_US
dc.identifier.issue6en_US
dc.identifier.spage729en_US
dc.identifier.epage740en_US
dc.identifier.eissn1524-4539-
dc.identifier.isiWOS:000307472600019-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridWang, Y=55295978900en_US
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_US
dc.identifier.scopusauthoridWu, D=55295551500en_US
dc.identifier.scopusauthoridXu, A=55295390500en_US
dc.identifier.scopusauthoridLee, MYK=55295927600en_US
dc.identifier.scopusauthoridXu, C=55245075900en_US
dc.identifier.scopusauthoridLiang, Y=55273172800en_US
dc.identifier.scopusauthoridBai, B=55247646000en_US

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