Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells

Berndt, Alexander; Stein, Sokrates; Holy, Erik W.; Camici, Giovanni G.; Lohmann, Christine; Akhmedov, Alexander; Spescha, Remo D.; Elliott, Peter J.; Westphal, Christoph H.; Matter, Christian M.; Lüscher, Thomas F.; Tanner, Felix C.

doi:10.1093/cvr/cvq339

Cited by 99 publications

(84 citation statements)

References 49 publications

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“…While we did not investigate the exact transcriptional machinery engaged by mitochondrial NADH shuttling, we demonstrate using two different cell types that increased SIRT1 expression occurs during physiologic Ca 2ϩ signaling and SIRT1 upregulation is linked to a mitochondrion-directed decrease in the cytosolic NAD ϩ /NADH ratio. Endothelial SIRT1 targets multiple proteins to effectively modulate nitric oxide production (75,76), inflammation (47,77,78), and vessel growth (79,80). Thus, SIRT1 expression is widely considered a positive effector of EC function.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Marcu

Wiczer

Neeley

et al. 2014

Molecular and Cellular Biology

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Mitochondrial calcium uptake stimulates bioenergetics and drives energy production in metabolic tissue. It is unknown how a calcium-mediated acceleration in matrix bioenergetics would influence cellular metabolism in glycolytic cells that do not require mitochondria for ATP production. Using primary human endothelial cells (ECs), we discovered that repetitive cytosolic calcium signals (oscillations) chronically loaded into the mitochondrial matrix. Mitochondrial calcium loading in turn stimulated bioenergetics and a persistent elevation in NADH. Rather than serving as an impetus for mitochondrial ATP generation, matrix NADH rapidly transmitted to the cytosol to influence the activity and expression of cytosolic sirtuins, resulting in global changes in protein acetylation. In endothelial cells, the mitochondrion-driven reduction in both the cytosolic and mitochondrial NAD ؉ / NADH ratio stimulated a compensatory increase in SIRT1 protein levels that had an anti-inflammatory effect. Our studies reveal the physiologic importance of mitochondrial bioenergetics in the metabolic regulation of sirtuins and cytosolic signaling cascades.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Marcu

Wiczer

Neeley

et al. 2014

Molecular and Cellular Biology

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“…3). 83 In vitro, SIRT1 diminishes tissue factor expression by deacetylating RelA/p65 and suppressing NFκB signaling in HAECs. SIRT1 inhibition or siRNA-mediated SIRT1 silencing in HAECs stimulated with inflammatory mediators increased tissue factor expression.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Protective roles of SIRT1 in atherosclerosis

2011

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“…Zeng et al reported that SIRT1 knockdown induced hepatic inflammation by increasing the activation of NF-κB [40]. Breitenstein et al reported that SIRT1 inhibition enhanced NF-κB activation via acetylation of Lys310 NF-κB /p65 in human aortic endothelial cells [41]. To investigate the effect of SIRT1 deletion on NF-κB in HUVECs, we only silenced SIRT1 expression via transfection of SIRT1 siRNA and then evaluated p65 expression in both cytosol and nuclear fractions.…”

Section: Discussionmentioning

confidence: 99%

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

Kim

Piao

Jung

2018

Journal of Hypertension

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AimsCR6 interacting factor 1 (CRIF1) deficiency impairs mitochondrial oxidative phosphorylation complexes, contributing to increased mitochondrial and cellular reactive oxygen species (ROS) production. CRIF1 downregulation has also been revealed to decrease sirtuin 1 (SIRT1) expression and impair vascular function. Inhibition of SIRT1 disturbs oxidative energy metabolism and stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-induced inflammation. Therefore, we hypothesized that both CRIF1 deficiency-induced mitochondrial ROS production and SIRT1 reduction play stimulatory roles in vascular inflammation. Methods and resultsPlasma levels and mRNA expression of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) were markedly elevated in endothelium-specific CRIF1-knockout mice and CRIF1-silenced endothelial cells, respectively. Moreover, CRIF1 deficiency-induced vascular adhesion molecule-1 (VCAM-1) expression was consistently attenuated by the antioxidant N-acetyl-cysteine and NF-κB inhibitor (BAY11). We next showed that siRNA-mediated CRIF1 downregulation markedly activated NF-κB. SIRT1 overexpression not only rescued CRIF1 deficiency-induced NF-κB activation but also decreased inflammatory cytokines (TNF-α, IL-1β, and IL-6) and VCAM-1 expression levels in endothelial cells. ConclusionsThese results strongly suggest that CRIF1 deficiency promotes endothelial cell inflammation by increasing VCAM-1 expression, elevating inflammatory cytokines levels, and activating the transcription factor NF-κB, all of which were inhibited by SIRT1 overexpression.

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Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells

Cited by 99 publications

References 49 publications

Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Protective roles of SIRT1 in atherosclerosis

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

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Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells

Cited by 99 publications

References 49 publications

Mitochondrial Matrix Ca2+ Accumulation Regulates Cytosolic NAD+/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Mitochondrial Matrix Ca2+ Accumulation Regulates Cytosolic NAD+/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Protective roles of SIRT1 in atherosclerosis

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

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Product

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Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

Mitochondrial Matrix Ca²⁺ Accumulation Regulates Cytosolic NAD⁺/NADH Metabolism, Protein Acetylation, and Sirtuin Expression