دورية أكاديمية
أعرض في EDS

Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice.

التفاصيل البيبلوغرافية
العنوان: Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice.
المؤلفون: Zetterqvist AV; Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden., Berglund LM, Blanco F, Garcia-Vaz E, Wigren M, Dunér P, Andersson AM, To F, Spegel P, Nilsson J, Bengtsson E, Gomez MF
المصدر: PloS one [PLoS One] 2013 Jun 03; Vol. 8 (6), pp. e65020. Date of Electronic Publication: 2013 Jun 03 (Print Publication: 2014).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science
مواضيع طبية MeSH: Disease Progression*, Atherosclerosis/*complications , Atherosclerosis/*pathology , Diabetes Mellitus, Experimental/*complications , Diabetes Mellitus, Experimental/*metabolism , NFATC Transcription Factors/*antagonists & inhibitors, Animals ; Aorta, Thoracic/metabolism ; Aorta, Thoracic/pathology ; Apolipoproteins E/deficiency ; Apolipoproteins E/metabolism ; Atherosclerosis/blood ; Biomarkers/metabolism ; Blood Glucose/metabolism ; Body Weight/drug effects ; Cholesterol/blood ; Diabetes Mellitus, Experimental/blood ; Diabetes Mellitus, Experimental/pathology ; Inflammation/pathology ; Interleukin-6/blood ; Mice, Inbred C57BL ; Monocytes/metabolism ; NFATC Transcription Factors/metabolism ; Plaque, Atherosclerotic/metabolism ; Plaque, Atherosclerotic/pathology ; Pyrazoles/pharmacokinetics ; Pyrazoles/pharmacology ; Signal Transduction/drug effects ; Transcription, Genetic/drug effects
مستخلص: Objective of the Study: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.
Methodology and Principal Findings: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice.
Conclusions: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications.
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المشرفين على المادة: 0 (A 285222)
0 (Apolipoproteins E)
0 (Biomarkers)
0 (Blood Glucose)
0 (Interleukin-6)
0 (NFATC Transcription Factors)
0 (Pyrazoles)
97C5T2UQ7J (Cholesterol)
تواريخ الأحداث: Date Created: 20130612 Date Completed: 20150128 Latest Revision: 20211021
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3670844
DOI: 10.1371/journal.pone.0065020
PMID: 23755169
قاعدة البيانات: MEDLINE
الوصف
تدمد:1932-6203
DOI:10.1371/journal.pone.0065020