CR6-Interacting Factor 1 Deficiency Impairs Vascular Function by Inhibiting the Sirt1-Endothelial Nitric Oxide Synthase Pathway

Nagar, Harsha; Jung, Sungyup; Ryu, Min Jeong; Choi, Sejong; Piao, Shuyu; Song, Hee‐Jung; Kang, Shin Kwang; Shin, Nara; Kim, Dong Ho; Jin, Seong Eun; Jeong, Jin‐Ok; Irani, Kaikobad; Jeon, Byeong Hwa; Shong, Minho; Kweon, Gi Ryang; Seong, In Whan

doi:10.1089/ars.2016.6719

Cited by 25 publications

(25 citation statements)

References 47 publications

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“…The data are presented as means ± SEM of three independent experiments. Crif1 deficiency promotes endothelial inflammation [19]. However, we have not investigated whether CRIF1 downregulation in endothelial cells is capable of triggering inflammatory responses via mitochondrial-derived ROS or other mechanisms.…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

Kim

Piao

Jung

2018

Journal of Hypertension

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“…Uncoupled eNOS in endothelial cells has been linked to decreased levels of BH4, which contributes to induced superoxide production instead of NO production in vascular diseases 26 . While we have previously described the effect of CRIF1 deficiency on ROS generation and eNOS inactivation in endothelial cells 22 , it is interesting to explore whether BH4-mediated ROS is associated with the vascular damage in CRIF1 downregulated cells. In this study, ROS production in CRIF1-deficient cells was reduced by treatment with the eNOS inhibitor L-NAME ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously described that CRIF1-deficiency-induced mitochondrial dysfunction impaired vascular function by the Sirt1-eNOS pathway 22 . The present study highlights that decreased eNOS/NO production was caused by reduced BH4 levels.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies showed that mitochondrial-specific O 2 − scavenger Mito-TEMPO treatment rescued the NO levels that were reduced by CRIF1 deletion 22 . In this study, we revealed that BH4 supplements could also improve endothelial function by activating the Akt/eNOS/NO pathway.…”

Section: Ros Mediated Crif1-deficiency-induced Enos Uncoupling In Huvmentioning

confidence: 96%

“…balance and mitochondrial function in endothelial cells and contributed to a higher concentration of ROS 22 . The increase in ROS may result from increased superoxide production or from uncoupled eNOS with reduced NO production.…”

Section: Crif1 Deficiency Induced Enos Uncoupling In Huvecs Crif1 Knmentioning

confidence: 99%

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CR6-interacting factor 1 deficiency reduces endothelial nitric oxide synthase activity by inhibiting biosynthesis of tetrahydrobiopterin

Lee

Kim

Nagar

et al. 2020

Sci Rep

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Downregulation of CR6 interacting factor 1 (CRIF1) has been reported to induce mitochondrial dysfunction, resulting in reduced activity of endothelial nitric oxide synthase (eNOS) and NO production in endothelial cells. Tetrahydrobiopterin (BH4) is an important cofactor in regulating the balance between NO (eNOS coupling) and superoxide production (eNOS uncoupling). However, whether the decreased eNOS and NO production in CRIF1-deficient cells is associated with relative BH4 deficiencyinduced eNOS uncoupling remains completely unknown. Our results showed that CRIF1 deficiency increased eNOS uncoupling and depleted levels of total biopterin and BH4 by reducing the enzymes of BH4 biosynthesis (GCH-1, PTS, SPR, and DHFR) in vivo and vitro, respectively. Supplementation of CRIF1-deficient cells with BH4 significantly increased the recovery of Akt and eNOS phosphorylation and NO synthesis. In addition, scavenging ROS with MitoTEMPO treatment replenished BH4 levels by elevating levels of GCH-1, PTS, and SPR, but with no effect on the level of DHFR. Downregulation of DHFR synthesis regulators p16 or p21 in CRIF1-deficient cells partially recovered the DHFR expression. In summary, CRIF1 deficiency inhibited BH4 biosynthesis and exacerbated eNOS uncoupling. This resulted in reduced NO production and increased oxidative stress, which contributes to endothelial dysfunction and is involved in the pathogenesis of cardiovascular diseases.

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B Cell–Specific Deletion of CR6‐Interacting Factor 1 Drives Lupus‐like Autoimmunity by Activation of Interleukin‐17, Interleukin‐6, and Pathogenic Follicular Helper T Cells in a Mouse Model

Park

Yang

Hwang

et al. 2022

Arthritis & Rheumatology

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Objective CR6‐interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein; however, its functions in B lymphocytes have been poorly defined. This study was undertaken to investigate the effects of CRIF1 on B cell metabolic regulation, cell function, and autoimmune diseases. Methods Using mice with B cell–specific deletion of CRIF1 (Crif1ΔCD19 mice), we assessed the relevance of CRIF1 function for lupus disease parameters, including anti–double‐stranded DNA (anti‐dsDNA), cytokines, and kidney pathology. RNA sequencing was performed on B cells from Crif1ΔCD19 mice. The phenotypic and metabolic changes in immune cells were evaluated in Crif1ΔCD19 mice. Roquinsan/+ mice crossed with Crif1ΔCD19 mice were monitored to assess the functionality of CRIF1‐deficient B cells in lupus development. Results Crif1ΔCD19 mice showed an autoimmune lupus‐like phenotype, including high levels of autoantibodies to dsDNA and severe lupus nephritis with increased mesangial hypercellularity. While loss of CRIF1 in B cells showed impaired mitochondrial oxidative function, CRIF1‐deficient B cells promoted the production of interleukin‐17 (IL‐17) and IL‐6 and was more potent in helping T cells develop into follicular helper T cells. In a mouse model of autoimmune lupus, depletion of CRIF1 in B cells exacerbated lupus severity, and CRIF1 overexpression prevented lupus development in roquinsan/san mice. Conclusion These results demonstrated that CRIF1 negatively correlates with disease severity and that overexpression of CRIF1 ameliorates disease development. Our findings suggest that CRIF1 is essential for preventing lupus development by maintaining B cell self tolerance.

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CR6-Interacting Factor 1 Deficiency Impairs Vascular Function by Inhibiting the Sirt1-Endothelial Nitric Oxide Synthase Pathway

Abstract: These findings indicate that CRIF1 plays an important role in maintaining mitochondrial and endothelial function through its effects on the SIRT1-eNOS pathway. Antioxid. Redox Signal. 27, 234-249.

Cited by 25 publications

References 47 publications

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

Cr6 Interacting Factor 1 Deficiency Promotes Endothelial Inflammation by Sirt1 Downregulation

CR6-interacting factor 1 deficiency reduces endothelial nitric oxide synthase activity by inhibiting biosynthesis of tetrahydrobiopterin

B Cell–Specific Deletion of CR6‐Interacting Factor 1 Drives Lupus‐like Autoimmunity by Activation of Interleukin‐17, Interleukin‐6, and Pathogenic Follicular Helper T Cells in a Mouse Model

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