Tweak up-regulates endothelin-1 system in mouse and human endothelial cells

Martínez-Miguel, Patricia; Medrano-Andrés, Diana; Griera-Merino, Mercedes; Ortíz, Alberto; Rodrı́guez-Puyol, Manuel; Rodríguez‐Puyol, Diego; López‐Ongil, Susana

doi:10.1093/cvr/cvw239

Cited by 24 publications

(13 citation statements)

References 52 publications

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“…Cells were grown in Dulbecco's Modified Eagle Media (DMEM) containing 4.5 g L −1 glucose and supplemented with 10% fetal bovine serum, 100 U mL −1 penicillin, and 100 μg mL −1 streptomycin in an atmosphere of 95% air and 5% CO 2 . Supernatants were collected to measure ET‐1 by ELISA (López‐Ongil et al ., ; Martínez‐Miguel et al ., ).…”

Section: Methodsmentioning

confidence: 97%

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

et al. 2017

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SummaryHyperphosphatemia is related to some pathologies, affecting vascular cell behavior. This work analyzes whether high concentration of extracellular phosphate induces endothelial senescence through up‐regulation of endothelin‐1 (ET‐1), exploring the mechanisms involved. The phosphate donor β‐glycerophosphate (BGP) in human endothelial cells increased ET‐1 production, endothelin‐converting enzyme‐1 (ECE‐1) protein, and mRNA expression, which depend on the AP‐1 activation through ROS production. In parallel, BGP also induced endothelial senescence by increasing p16 expression and the senescence‐associated β‐galactosidase (SA‐ß‐GAL) activity. ET‐1 itself was able to induce endothelial senescence, increasing p16 expression and SA‐ß‐GAL activity. In addition, senescence induced by BGP was blocked when different ET‐1 system antagonists were used. BGP increased ROS production at short times, and the presence of antioxidants prevented the effect of BGP on AP1 activation, ECE‐1 expression, and endothelial senescence. These findings were confirmed in vivo with two animal models in which phosphate serum levels were increased: seven/eight nephrectomized rats as chronic kidney disease models fed on a high phosphate diet and aged mice. Both models showed hyperphosphatemia, higher levels of ET‐1, and up‐regulation in aortic ECE‐1, suggesting a direct relationship between hyperphosphatemia and ET‐1. Present results point to a new and relevant role of hyperphosphatemia on the regulation of ET‐1 system and senescence induction at endothelial level, both in endothelial cells and aorta from two animal models. The mechanism involved showed a higher ROS production, which probably activates AP‐1 transcription factor and, as a result, ECE‐1 expression, increasing ET‐1 synthesis, which in consequence induces endothelial senescence.

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Section: Methodsmentioning

confidence: 97%

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

et al. 2017

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“…In addition, endothelin-1 plays a very important functional role in progression of systemic sclerosis ( 304 , 305 ). This endothelin-1 expression is also regulated by JNK/AP1 and NFκB pathways ( 306 – 308 ). As mentioned above, IRE1α activation increases the JNK/AP1 and NFκB pathways-mediated transcription.…”

Section: Ire1α Involvement In Autoimmune and Inflammatory Diseasesmentioning

confidence: 99%

IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

et al. 2018

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Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) is the most prominent and evolutionarily conserved endoplasmic reticulum (ER) membrane protein. This transduces the signal of misfolded protein accumulation in the ER, named as ER stress, to the nucleus as “unfolded protein response (UPR).” The ER stress-mediated IRE1α signaling pathway arbitrates the yin and yang of cell life. IRE1α has been implicated in several physiological as well as pathological conditions, including immune disorders. Autoimmune diseases are caused by abnormal immune responses that develop due to genetic mutations and several environmental factors, including infections and chemicals. These factors dysregulate the cell immune reactions, such as cytokine secretion, antigen presentation, and autoantigen generation. However, the mechanisms involved, in which these factors induce the onset of autoimmune diseases, are remaining unknown. Considering that these environmental factors also induce the UPR, which is expected to have significant role in secretory cells and immune cells. The role of the major UPR molecule, IRE1α, in causing immune responses is well identified, but its role in inducing autoimmunity and the pathogenesis of autoimmune diseases has not been clearly elucidated. Hence, a better understanding of the role of IRE1α and its regulatory mechanisms in causing autoimmune diseases could help to identify and develop the appropriate therapeutic strategies. In this review, we mainly center the discussion on the molecular mechanisms of IRE1α in the pathophysiology of autoimmune diseases.

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“…While some studies show that increased TWEAK levels indicate vascular damage, indirect evidence suggests that TWEAK may contribute to the development of atherosclerosis in inflammatory or metabolic diseases by increasing endothelin synthesis. 20 Recent studies on the pathogenesis of RA have drawn attention to the sTWEAK/ Fn14 pathway. TWEAK is a member of the TNF superfamily that is structurally related to cytokines and is a protein that exhibits cytotoxic and pro-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

The Evaluation of Serum Tumor Necrosis Factor-Like Weak Inducer of Apoptosis, Interleukin-6, Fetuin-A, Homeostatic Model Assessment-Insulin Resistance, and Insulin Levels in Rheumatoid Arthritis Patients in Clinical Remission

et al. 2019

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Objectives: This study aims to examine the relationship of serum tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels with interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), fetuin-A, insulin, homeostatic model assessment (HOMA)-insulin resistance (IR), and disease activity in patients with rheumatoid arthritis (RA) who are in remission or have low disease activity. Patients and methods: Fifty-four patients with RA (8 males, 46 females; mean age 52.7±12.3 years; range 40 to 64 years) and 34 healthy controls (6 males, 28 females; mean age 53.2±11.3 years; range 41 to 65 years) were included in the study. The sTWEAK, fetuin-A, insulin, lipid profile and IL-6 concentrations were determined. The HOMA-IR levels were calculated using a calculator. Disease activity score 28 was used to assess the disease activity. Results: The erythrocyte sedimentation rate, C-reactive protein, fetuin-A, and IL-6 levels were higher in the RA group than in the control group (p=0.004, 0.001, 0.001, and 0.003, respectively). sTWEAK levels were lower in the RA group than in the control group (p=0.007). There were no differences in the TNF-α, HOMA-IR, insulin, and lipid profile levels of the two groups (p>0.05). sTWEAK had a negative correlation with body mass index and fetuin-A (r=-0.261 and r=-0.287, respectively). Conclusion: We found that RA patients had lower sTWEAK levels and higher fetuin-A levels than the control group subjects. Furthermore, these two molecules were associated with each other. This study demonstrated that in RA patients, even if the disease is controlled with treatment, some molecules associated with an increased metabolic and cardiovascular risk continue to function. Follow-up studies on larger populations are warranted to confirm these findings.

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Tweak up-regulates endothelin-1 system in mouse and human endothelial cells

Abstract: In pathological situations such as chronic inflammation, TWEAK could be more harmful through this effect at endothelial level. Pharmacological blockade of this cytokine could prevent the haemodynamic and structural changes related to an increased ET-1 synthesis.

Cited by 24 publications

References 52 publications

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production

IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

The Evaluation of Serum Tumor Necrosis Factor-Like Weak Inducer of Apoptosis, Interleukin-6, Fetuin-A, Homeostatic Model Assessment-Insulin Resistance, and Insulin Levels in Rheumatoid Arthritis Patients in Clinical Remission

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