CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation

• Published in: PloS one Vol. 13; no. 2; p. e0192693
• Main Authors: Piao, Shuyu, Lee, Jun Wan, Nagar, Harsha, Jung, Saet-byel, Choi, Sujeong, Kim, Seonhee, Lee, Ikjun, Kim, Sung-min, Shin, Nara, Lee, Yu Ran, Lee, Sang Do, Park, Jin Bong, Irani, Kaikobad, Won, Minho, Hur, Gang Min, Jeon, Byeong Hwa, Kim, Dong Woon, Kim, Cuk-Seong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.02.2018; Public Library of Science (PLoS)
• Subjects: Anatomy & physiology; Antioxidants; Atherosclerosis; Biology and Life Sciences; Cell adhesion & migration; Cellular manufacture; Cytokines; Development and progression; Endothelial cells; Endothelium; Energy metabolism; Gene expression; Genetic aspects; Growth factors; Inflammation; Inhibition; Interleukin; Interleukin 6; Interleukins; Lymphocytes B; Medicine; Medicine and Health Sciences; Metabolism; Mitochondria; NF-κB protein; Nitric oxide; Oxidative metabolism; Oxidative phosphorylation; Oxidative stress; Oxygen; Pharmacology; Phosphorylation; Physiological aspects; Physiology; Plasma levels; Reactive oxygen species; Research and Analysis Methods; Rodents; siRNA; SIRT1 protein; Thrombosis; Transcription factors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vascular cell adhesion molecule 1; South Korea; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0192693

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-κB)-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)-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. 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-κB, all of which were inhibited by SIRT1 overexpression.