Dataset Information

Ca2+/calmodulin-dependent protein kinase kinase ? 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)? 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 CaMKK?. Flow-enhanced SIRT1 stability was primarily mediated by CaMKK? 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 CaMKK? phosphorylation of SIRT1 Ser-27 and Ser-47 increased antioxidative and anti-inflammatory capacities. Ablation of CaMKK? 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 CaMKK?-SIRT1 axis in ECs is mechanosensitive, antioxidative, and anti-inflammatory.

SUBMITTER: Wen L

PROVIDER: S-EPMC3696824 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Ca2+/calmodulin-dependent protein kinase kinase β phosphorylation of Sirtuin 1 in endothelium is atheroprotective.

Wen Liang L Chen Zhen Z Zhang Fan F Cui Xiaopei X Sun Wei W Geary Greg G GG Wang Yinsheng Y Johnson David A DA Zhu Yi Y Chien Shu S Shyy John Y-J JY

Proceedings of the National Academy of Sciences of the United States of America 20130610 26

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 in ...[more]

PMID: 23754392

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Project description:During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning.

Dataset Information

Ca2+/calmodulin-dependent protein kinase kinase ? phosphorylation of Sirtuin 1 in endothelium is atheroprotective.

Publications

Ca2+/calmodulin-dependent protein kinase kinase β phosphorylation of Sirtuin 1 in endothelium is atheroprotective.

Similar Datasets

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