CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation.

ABSTRACT: CR6 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-?B)-induced inflammation. Therefore, we hypothesized that both CRIF1 deficiency-induced mitochondrial ROS production and SIRT1 reduction play stimulatory roles in vascular inflammation.Plasma levels and mRNA expression of proinflammatory cytokines (tumor necrosis factor (TNF)-?, interleukin (IL)-1?, 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-?B inhibitor (BAY11). We next showed that siRNA-mediated CRIF1 downregulation markedly activated NF-?B. SIRT1 overexpression not only rescued CRIF1 deficiency-induced NF-?B activation but also decreased inflammatory cytokines (TNF-?, IL-1?, and IL-6) and VCAM-1 expression levels in endothelial cells.These 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-?B, all of which were inhibited by SIRT1 overexpression.

SUBMITTER: Piao S 

PROVIDER: S-EPMC5825004 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature