CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction

Venkatesan, Balachandar; Valente, Anthony J.; Das, Nitin A.; Carpenter, Andrea J.; Yoshida, Tadashi; Delafontaine, Jean Luc; Siebenlist, Ulrich; Chandrasekar, Bysani

doi:10.1016/j.cellsig.2012.10.009

Cited by 40 publications

(63 citation statements)

References 44 publications

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“…In diabetes, high glucose-stimulated cytokines of inflammation leading to dysfunction of endothelial cells by oxidative stress enhancement, raising inflammatory cells leakage and inducement of adhesion molecules on endothelial cells and monocytes [19].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics: Inflammatory Cytokines and Attenuation of Diabetes Hypercholesterolemia-Induced Renal Injury Using Morning Glory and Necklace Pod Extracts

Aly

Abd‐Alla²,

Ali³

et al. 2017

Asian J Pharm Clin Res

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Objective: The present research in bioinformatics focuses on pharmacological effects of morning glory and necklace pod ethanolic extracts (MGE and NPE) on some biochemical parameters in high fat diet-induced hypercholesterolemia and streptozotocin-induced hyperglycemia in rats.Methods: Compared to atorvastatin; an anti-hypercholesterolemic (HC) and glibenclamide; an antidiabetic drug. Endothelium activation markers of soluble vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 were determined using enzyme-linked immunosorbent assay. Creatinine, urea, and inflammatory biomarkers; C-reactive protein (CRP) and pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin (IL)-10 levels were also measured in serum of different therapeutic groups.Results: Significant decrease in ICAM-1 level with MGE and NPE supplemented to normal rats as compared to untreated control with percentages decrease 17.80 and 12.00% was observed. Insignificant change was detected in VCAM-1 level. Profound amelioration in CRP, total urea and creatinine levels by NPE treatment. Creatinine, urea, CRP, and TNF-α level were significantly increased in hyperglycemic (HG)-HC rats. However, IL-10 level showed a significant decrease. Meanwhile, histopathological investigation of the kidney and heart was carried out. Image recognition system for kidney and heart images was developed to diagnose their diseases. Tested extract attenuated creatinine, urea, CRP, and TNF-α level. Hyperglycemia and hypercholesterolemia linked kidney disorders were relieved. Conclusion:In vivo oral administration with each extract declared suppression of cytokines mediated inflammation, vascular function leading to infiltration reduction of renal macrophage together with lowering in kidney indices and ameliorate renal tissues architectures in HG-HC rats.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics: Inflammatory Cytokines and Attenuation of Diabetes Hypercholesterolemia-Induced Renal Injury Using Morning Glory and Necklace Pod Extracts

Aly

Abd‐Alla²,

Ali³

et al. 2017

Asian J Pharm Clin Res

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“…Factors, including increased nitroxidative stress, inflammation, intracellular Ca 2ϩ overload, shift in pH, opening of mitochondrial permeability transition pore, endothelial dysfunction, microvascular injury, and altered metabolism, all acting in concert contribute to its pathogenesis (1,28 (36 -38). Because TRAF3IP2 is an upstream regulator of these transcription factors (18,19), it is highly likely that Traf3ip2 gene deletion might have resulted in reduced expres- sion and/or activation of these critical enzymes. We have also shown that Traf3ip2 gene deletion inhibited Nos2 expression, also a NF-B-responsive gene (39), in the heart post-I/R.…”

Section: Discussionmentioning

confidence: 99%

“…Expressions of proteins that were below detection level and those that did not show a significant difference were excluded from the results in Table 2. Preparation of protein homogenates, immunoblotting, and densitometry were performed as described previously (17,19,20,26). The source and concentration of antibodies used in immunoblotting are previously described (17,19,20,26,57).…”

Section: Methodsmentioning

confidence: 99%

“…Its promoter region contains potential binding sites for AP-1, NF-B, C/EBP␤, CREB, and IRF1 (18,19), indicating that oxidative stress induces TRAF3IP2 expression, and upon induction, it may regulate its own expression and that of multiple inflammatory mediators, ultimately resulting in tissue injury and dysfunction. In fact, we have previously demonstrated that advanced oxidation protein products, which serve as markers of oxidative stress and mediators of inflammation, induce cardiomyocyte death in part via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling (20).…”

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confidence: 99%

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Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling

Erikson

Valente

Mummidi

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerRe-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-B and JNK/ AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destructionmediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-B and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.Ischemic heart disease is a leading cause of morbidity and mortality worldwide (1). Although reperfusion of the ischemic myocardium is the primary goal of reducing myocardial injury and dysfunction, paradoxically it can also produce pathological effects by the (i) excessive generation of reactive oxygen and nitrogen species, (ii) activation of the redox-sensitive dimeric transcription factors NF-B and AP-1, (iii) up-regulation of inflammatory mediators, (iv) recruitment and activation of immune and inflammatory cells, and (v) induction of cardiomyocyte apoptosis, which ultimately results in myocardial injury, dysfunction (ischemia/reperfusion injury or I/R injury), and adverse remodeling (2, 3). Despite progress in our understanding of its underlying molecular mechanisms, myocardial injury post-I/R remains an important clinical problem.A number of studies have firmly established causal roles for the nuclear transcription factors NF-B and AP-1 in myocardial I/R injury (4 -12). Various stimuli, including oxidative stress, cytokines, and growth factors, activate NF-B by inducing the hyperphosphorylation and degradation of its inhibitory subunit IB. A multiprotein complex comprised of IKK␣, IKK␤, and a regulatory subunit IK...

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“…Confluent IEC-6 and Caco-2 cells were thus placed in low glucose medium (1 mmol/L) for 3 h to mimic preprandial conditions. Thereafter, cells were stimulated by 25 mmol/L of D-glucose, a concentration recorded in postprandial situations (Iannello et al 2005;Manea et al 2013;Venkatesan et al 2013). As shown in Fig.…”

Section: P2x7 Receptor Mrna Expression Is Increased Following Glucosementioning

confidence: 99%

C/EBPβ regulates P2X7 receptor expression in response to glucose challenge in intestinal epithelial cells

BilodeauMaude

ArguinGuillaume

GendronFernand-Pierre

2015

Biochem. Cell Biol.

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Activation of the ATP-dependent P2X7 receptor modulates glucose transport in intestinal epithelial cells through the downregulation of glucose transporter GLUT2. In the present study, we show that an increase in glucose concentration stimulates P2X7 receptor transcription via modulation of CCAAT/enhancer binding proteins (C/EBPs) α and β expression. The described human P2X7 receptor promoter region (GenBank Y12851) was cloned upstream of a luciferase reporter gene in pGL4.10 plasmid and used to determine whether C/EBPs, namely C/EBPα and C/EBPβ, are able to stimulate the transcription of P2X7 receptor. Results show that C/EBPβ was the main regulator of P2X7 receptor expression in response to a glucose challenge. Chromatin immunoprecipitation (ChIP) assays further revealed that C/EBPβ occupied the -213 to +6 nt P2X7 promoter region. Surprisingly, C/EBPα was also able to bind this region as revealed by ChIP assays, but without inducing receptor transcription. In fact, C/EBPα and the C/EBPβ-LIP isoform blocked the C/EBPβ-dependent regulation of P2X7 receptor transcription. These findings suggest that glucose is not only the major source of energy for cell function but may also act as a signaling molecule to stimulate the expression of regulatory proteins.

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CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction

Cited by 40 publications

References 44 publications

Bioinformatics: Inflammatory Cytokines and Attenuation of Diabetes Hypercholesterolemia-Induced Renal Injury Using Morning Glory and Necklace Pod Extracts

Bioinformatics: Inflammatory Cytokines and Attenuation of Diabetes Hypercholesterolemia-Induced Renal Injury Using Morning Glory and Necklace Pod Extracts

Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling

C/EBPβ regulates P2X7 receptor expression in response to glucose challenge in intestinal epithelial cells

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