Matches in SemOpenAlex for { <https://semopenalex.org/work/W3114927754> ?p ?o ?g. }
- W3114927754 endingPage "491" @default.
- W3114927754 startingPage "474" @default.
- W3114927754 abstract "Rationale: Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage and telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation, and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear. Objective: We examined SIRT6 expression in human VSMCs, the role, regulation, and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis. Methods and Results: SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in human VSMCs derived from plaques or undergoing replicative or palmitate-induced senescence versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus of HSC70-interacting protein) promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6 H133Y ) shortened human VSMC lifespan and induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation and 53BP1 (p53 binding protein 1) binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6 H133Y , promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE −/− (apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6 H133Y in VSMCs only. SM22α-hSIRT6/ApoE −/− mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6 H133Y /ApoE −/− mice showed increased features of plaque instability. Conclusions: SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan and inhibits atherogenesis, all dependent on its deacetylase activity. Our data show that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis." @default.
- W3114927754 created "2021-01-05" @default.
- W3114927754 creator A5014538781 @default.
- W3114927754 creator A5041214742 @default.
- W3114927754 creator A5049019972 @default.
- W3114927754 creator A5067198585 @default.
- W3114927754 creator A5089978523 @default.
- W3114927754 date "2021-02-19" @default.
- W3114927754 modified "2023-10-14" @default.
- W3114927754 title "SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis" @default.
- W3114927754 cites W1978327824 @default.
- W3114927754 cites W1981525849 @default.
- W3114927754 cites W1990909446 @default.
- W3114927754 cites W2020311873 @default.
- W3114927754 cites W2029969982 @default.
- W3114927754 cites W2038881106 @default.
- W3114927754 cites W2041836907 @default.
- W3114927754 cites W2063084036 @default.
- W3114927754 cites W2063679739 @default.
- W3114927754 cites W2078340601 @default.
- W3114927754 cites W2080290533 @default.
- W3114927754 cites W2106729288 @default.
- W3114927754 cites W2109560454 @default.
- W3114927754 cites W2112886810 @default.
- W3114927754 cites W2133678645 @default.
- W3114927754 cites W2135804517 @default.
- W3114927754 cites W2147671485 @default.
- W3114927754 cites W2150050786 @default.
- W3114927754 cites W2159652870 @default.
- W3114927754 cites W2172797119 @default.
- W3114927754 cites W2253189741 @default.
- W3114927754 cites W2313646508 @default.
- W3114927754 cites W2415755712 @default.
- W3114927754 cites W2417775236 @default.
- W3114927754 cites W2510888821 @default.
- W3114927754 cites W2544670169 @default.
- W3114927754 cites W2593375060 @default.
- W3114927754 cites W2758507511 @default.
- W3114927754 cites W2768499262 @default.
- W3114927754 cites W2792785502 @default.
- W3114927754 cites W2902510443 @default.
- W3114927754 cites W2911393219 @default.
- W3114927754 cites W2924884438 @default.
- W3114927754 cites W2937386865 @default.
- W3114927754 cites W2952633727 @default.
- W3114927754 cites W2955108563 @default.
- W3114927754 cites W2969883164 @default.
- W3114927754 cites W2995236678 @default.
- W3114927754 cites W2995817383 @default.
- W3114927754 cites W3003838625 @default.
- W3114927754 doi "https://doi.org/10.1161/circresaha.120.318353" @default.
- W3114927754 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7899748" @default.
- W3114927754 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33353368" @default.
- W3114927754 hasPublicationYear "2021" @default.
- W3114927754 type Work @default.
- W3114927754 sameAs 3114927754 @default.
- W3114927754 citedByCount "92" @default.
- W3114927754 countsByYear W31149277542021 @default.
- W3114927754 countsByYear W31149277542022 @default.
- W3114927754 countsByYear W31149277542023 @default.
- W3114927754 crossrefType "journal-article" @default.
- W3114927754 hasAuthorship W3114927754A5014538781 @default.
- W3114927754 hasAuthorship W3114927754A5041214742 @default.
- W3114927754 hasAuthorship W3114927754A5049019972 @default.
- W3114927754 hasAuthorship W3114927754A5067198585 @default.
- W3114927754 hasAuthorship W3114927754A5089978523 @default.
- W3114927754 hasBestOaLocation W31149277541 @default.
- W3114927754 hasConcept C104317684 @default.
- W3114927754 hasConcept C119157956 @default.
- W3114927754 hasConcept C134018914 @default.
- W3114927754 hasConcept C134459356 @default.
- W3114927754 hasConcept C143425029 @default.
- W3114927754 hasConcept C177336024 @default.
- W3114927754 hasConcept C203014093 @default.
- W3114927754 hasConcept C25602115 @default.
- W3114927754 hasConcept C2776914184 @default.
- W3114927754 hasConcept C2777595374 @default.
- W3114927754 hasConcept C2778305200 @default.
- W3114927754 hasConcept C2779395532 @default.
- W3114927754 hasConcept C2780561631 @default.
- W3114927754 hasConcept C2992686903 @default.
- W3114927754 hasConcept C522857546 @default.
- W3114927754 hasConcept C552990157 @default.
- W3114927754 hasConcept C55493867 @default.
- W3114927754 hasConcept C64927066 @default.
- W3114927754 hasConcept C86803240 @default.
- W3114927754 hasConcept C95444343 @default.
- W3114927754 hasConceptScore W3114927754C104317684 @default.
- W3114927754 hasConceptScore W3114927754C119157956 @default.
- W3114927754 hasConceptScore W3114927754C134018914 @default.
- W3114927754 hasConceptScore W3114927754C134459356 @default.
- W3114927754 hasConceptScore W3114927754C143425029 @default.
- W3114927754 hasConceptScore W3114927754C177336024 @default.
- W3114927754 hasConceptScore W3114927754C203014093 @default.
- W3114927754 hasConceptScore W3114927754C25602115 @default.
- W3114927754 hasConceptScore W3114927754C2776914184 @default.
- W3114927754 hasConceptScore W3114927754C2777595374 @default.
- W3114927754 hasConceptScore W3114927754C2778305200 @default.