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

Autor: Patricia Martínez-Miguel, Alberto Ortiz, Susana López-Ongil, Manuel Rodríguez-Puyol, Diana Medrano-Andrés, Diego Rodríguez-Puyol, Mercedes Griera-Merino
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
medicine.hormone
medicine.medical_specialty
Time Factors
Transcription
Genetic
Physiology
Angiogenesis
Endothelin converting enzyme 1
medicine.medical_treatment
Blood Pressure
Inflammation
Endothelin-Converting Enzymes
In Vitro Techniques
030204 cardiovascular system & hematology
Biology
Transfection
Cell Line
Endothelins
Mice
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
Internal medicine
medicine
Animals
Humans
RNA
Messenger
Promoter Regions
Genetic
education
education.field_of_study
Endothelin-1
NF-kappa B
Endothelial Cells
NFKB1
Endothelin 1
Up-Regulation
Transcription Factor AP-1
030104 developmental biology
Cytokine
Endocrinology
Hypertension
Tumor Necrosis Factors
Cancer research
medicine.symptom
Cardiology and Cardiovascular Medicine
Zdroj: Cardiovascular Research. 113:207-221
ISSN: 1755-3245
0008-6363
Popis: Aim To analyse the ability of TWEAK to modify the endothelin system, particularly endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1), studying the intracellular mechanisms implied. TNF-like weak inducer of apoptosis (TWEAK) is a member of TNF superfamily; it has different biological functions such as inflammation, angiogenesis, proliferation, and apoptosis. TWEAK and fibroblast growth-factor-inducible 14 are expressed in different cell types, including endothelial and smooth muscle cells. Despite their presence in endothelial cells, the effect of TWEAK on endothelial function is incompletely defined. Methods and results In cells, TWEAK induced protein (Western blot) and mRNA (quantitative polymerase chain reaction) expression of ECE-1. Results were related to transcriptional changes, as ECE-1 promoter activity (transfection assays) was also increased. Transfections with serial deletions of ECE-1 promoter suggest a potential role for AP-1 and NFkB, which were confirmed by electrophoretic mobility shift assays. When AP-1 or NFkB activations were inhibited by specific inhibitors of AP-1, PD-98059 (Erk1/2 inhibitor), or SP-600125 (JNK inhibitor), and also with an inhibitor of NFKB and PDTC, TWEAK effect was partially blocked in both cases, suggesting that both transcription factors are implied in ECE-1 regulation. Moreover, the endothelial changes induced by TWEAK were also tested in vivo , using 3-month-old male CD-1 mice treated with TWEAK 10 µg/kg body weight for 24 h, finding similar effects, a rise in ET-1 production (enzyme-linked immunosorbent assay), and ECE-1 expression in aorta and lung tissues. Mice showed slight hypertension after 4 h of treatment, which disappeared at 24 h. Conclusions 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.
Databáze: OpenAIRE
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