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Article: Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis
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TitleCyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis
 
AuthorsBai, B1
Liang, Y1
Xu, C1
Lee, MYK1
Xu, A1
Wu, D2
Vanhoutte, PM1
Wang, Y1
 
Issue Date2012
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
 
CitationCirculation, 2012, v. 126 n. 6 , p. 729-740 [How to Cite?]
DOI: http://dx.doi.org/10.1161/CIRCULATIONAHA.112.118778
 
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.
 
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
 
ISSN0009-7322
2013 Impact Factor: 14.948
 
DOIhttp://dx.doi.org/10.1161/CIRCULATIONAHA.112.118778
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorBai, B
 
dc.contributor.authorLiang, Y
 
dc.contributor.authorXu, C
 
dc.contributor.authorLee, MYK
 
dc.contributor.authorXu, A
 
dc.contributor.authorWu, D
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorWang, Y
 
dc.date.accessioned2012-10-30T06:14:21Z
 
dc.date.available2012-10-30T06:14:21Z
 
dc.date.issued2012
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
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.identifier.citationCirculation, 2012, v. 126 n. 6 , p. 729-740 [How to Cite?]
DOI: http://dx.doi.org/10.1161/CIRCULATIONAHA.112.118778
 
dc.identifier.doihttp://dx.doi.org/10.1161/CIRCULATIONAHA.112.118778
 
dc.identifier.eissn1524-4539
 
dc.identifier.epage740
 
dc.identifier.hkuros204677
 
dc.identifier.issn0009-7322
2013 Impact Factor: 14.948
 
dc.identifier.issue6
 
dc.identifier.pmid22753194
 
dc.identifier.scopuseid_2-s2.0-84864708402
 
dc.identifier.spage729
 
dc.identifier.urihttp://hdl.handle.net/10722/171450
 
dc.identifier.volume126
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circ.ahajournals.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofCirculation
 
dc.relation.referencesReferences in Scopus
 
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 atherosclerosis
 
dc.typeArticle
 
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<contributor.author>Liang, Y</contributor.author>
<contributor.author>Xu, C</contributor.author>
<contributor.author>Lee, MYK</contributor.author>
<contributor.author>Xu, A</contributor.author>
<contributor.author>Wu, D</contributor.author>
<contributor.author>Vanhoutte, PM</contributor.author>
<contributor.author>Wang, Y</contributor.author>
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<description.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.</description.abstract>
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<subject.mesh>Atherosclerosis - enzymology - pathology</subject.mesh>
<subject.mesh>Cell Aging - physiology</subject.mesh>
<subject.mesh>Cyclin-Dependent Kinase 5 - antagonists and inhibitors - physiology</subject.mesh>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Chinese Academy of Sciences