Research Article: CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation

Date Published: February 23, 2018

Publisher: Public Library of Science

Author(s): Shuyu Piao, Jun Wan Lee, Harsha Nagar, Saet-byel Jung, Sujeong Choi, Seonhee Kim, Ikjun Lee, Sung-min Kim, Nara Shin, Yu Ran Lee, Sang Do Lee, Jin Bong Park, Kaikobad Irani, Minho Won, Gang Min Hur, Byeong Hwa Jeon, Dong Woon Kim, Cuk-Seong Kim, Ramani Ramchandran.

http://doi.org/10.1371/journal.pone.0192693

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-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.

Partial Text

Endothelial cells, which are located in the inner monolayer of the blood vessels, play important roles in maintaining vascular homeostasis and regulating the circulatory system [1]. A considerable amount of research has shown that endothelial dysfunction is an early determinant of the development of many cardiovascular diseases such as hypertension, hypercholesterolemia, and atherosclerosis [1–3]. Mitochondria are present in relatively low concentration (2–6%) with low energy requirement in endothelial cells compared to other cell types [4]. Although mitochondria are not the major source of energy production in endothelial cells, they are the main cellular sites of reactive oxygen species (ROS) production and serve as important ROS regulator of intracellular signaling pathways [5, 6]. Many studies have strongly approved that increased mitochondrial ROS production would contribute to endothelial dysfunction in the setting of cardiovascular disease [7, 8]. Endothelial dysfunction in turn promotes vascular inflammation by inducing the production of adhesion molecules, like vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), inflammatory mediators like cytokines, and vasoconstrictors [9].

Vascular function and structural alterations may contribute to hypertension, atherosclerosis, diabetes mellitus, and other cardiovascular diseases [25, 26]. The endothelium regulates vascular tone and permeability by influencing the vascular function and remodeling [1]. Therefore, endothelial inflammation occurs in association with endothelial dysfunction and vascular remodeling, which leads to several cardiovascular diseases such as hypertension and atherosclerosis [9]. There is considerable evidence indicating that mitochondrial dysfunction contributes to endothelial dysfunction, which leads to oxidative stress and inflammation, resulting in vascular dysfunction and other diseases [5, 6]. Moreover, accumulating evidence supports that mitochondrial dysfunction generates inflammatory responses [27, 28]. CRIF1 is a mitochondrial protein and interacts with the 39S subunit of the mitoribosome, which is essential for the synthesis and insertion of OXPHOS polypeptides [10]. We have demonstrated that CRIF1 deficiency reduced OXPHOS expression accompanied by increased mitochondrial ROS expression, which decreased SIRT1 expression, eNOS activity and vasomotor function [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. The results of this study demonstrated that CRIF1 deficiency- elevated the levels of inflammatory mediators, including VCAM-1, TNF-α, IL-1β and IL-6 via the activation of NF-κB pathway (Fig 6). Furthermore, SIRT1 overexpression led to recovery of these inflammatory mediators by suppressing NF-κB activity.

 

Source:

http://doi.org/10.1371/journal.pone.0192693

 

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