title: Ca2+/calmodulin-dependent protein kinase kinase β phosphorylation of Sirtuin 1 in endothelium is atheroprotective.
abstract: Atheroprotective flow exerts antioxidative and anti-inflammatory effects on vascular endothelial cells (ECs), in part through the induction of Sirtuin 1 (SIRT1), a class III histone deacetylase. The role of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)β in flow induction of SIRT1 both in vitro and in vivo was investigated. Pulsatile shear stress mimicking atheroprotective flow increased the level of SIRT1 in cultured ECs by enhancing its stability, and this effect was abolished by inhibition or knockdown of CaMKKβ. Flow-enhanced SIRT1 stability was primarily mediated by CaMKKβ phosphorylation of SIRT1 at Ser-27 and Ser-47, as evidenced by in vitro kinase assay, mass spectrometry, and experiments using loss- or gain-of-function SIRT1 mutants. Flow-induced CaMKKβ phosphorylation of SIRT1 Ser-27 and Ser-47 increased antioxidative and anti-inflammatory capacities. Ablation of CaMKKβ or SIRT1 in mice with an apolipoprotein E-null background showed increased atherosclerosis both in athero-prone and in athero-protective areas. The results suggest that the CaMKKβ-SIRT1 axis in ECs is mechanosensitive, antioxidative, and anti-inflammatory.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Sciences Center, Beijing 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Cui
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Greg G
authors.initials: GG
authors.lastname: Geary
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055550:Protein Stability; D011673:Pulsatile Flow / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1