دورية أكاديمية
Inhibition of NFAT Signaling Restores Microvascular Endothelial Function in Diabetic Mice.
| العنوان: | Inhibition of NFAT Signaling Restores Microvascular Endothelial Function in Diabetic Mice. |
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| المؤلفون: | Garcia-Vaz E; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden., McNeilly AD; Division of Clinical and Molecular Medicine, Ninewells Hospital and University of Dundee, Dundee, U.K., Berglund LM; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden., Ahmad A; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden., Gallagher JR; Division of Clinical and Molecular Medicine, Ninewells Hospital and University of Dundee, Dundee, U.K., Dutius Andersson AM; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden., McCrimmon RJ; Division of Clinical and Molecular Medicine, Ninewells Hospital and University of Dundee, Dundee, U.K., Zetterqvist AV; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden., Gomez MF; Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Lund, Sweden maria.gomez@med.lu.se f.khan@dundee.ac.uk., Khan F; Division of Clinical and Molecular Medicine, Ninewells Hospital and University of Dundee, Dundee, U.K. maria.gomez@med.lu.se f.khan@dundee.ac.uk. |
| المصدر: | Diabetes [Diabetes] 2020 Mar; Vol. 69 (3), pp. 424-435. Date of Electronic Publication: 2019 Dec 05. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Alexandria, VA : American Diabetes Association Original Publication: [New York, American Diabetes Association] |
| مواضيع طبية MeSH: | Diabetes Mellitus, Experimental/*physiopathology , Endothelium, Vascular/*drug effects , Microvessels/*drug effects , NFATC Transcription Factors/*antagonists & inhibitors , Pyrazoles/*pharmacology, Acetylcholine/pharmacology ; Animals ; Blood Pressure/drug effects ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Endothelin-1/drug effects ; Endothelin-1/metabolism ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/physiopathology ; Enzyme Inhibitors/pharmacology ; Insulin/genetics ; Interleukin-6/metabolism ; Iontophoresis ; Mice ; Microvessels/metabolism ; Microvessels/physiopathology ; NFATC Transcription Factors/drug effects ; NFATC Transcription Factors/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase Type III/drug effects ; Nitric Oxide Synthase Type III/metabolism ; Nitroprusside/pharmacology ; Osteopontin/drug effects ; Osteopontin/metabolism ; Skin/blood supply ; Survival Rate ; Ultrasonography, Doppler ; Vasodilator Agents/pharmacology |
| مستخلص: | Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita ( Ins2 +/- ) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor l- N G -nitro-l-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes. (© 2019 by the American Diabetes Association.) |
| معلومات مُعتمدة: | PG/12/58/29767 United Kingdom BHF_ British Heart Foundation |
| المشرفين على المادة: | 0 (A 285222) 0 (Endothelin-1) 0 (Enzyme Inhibitors) 0 (Ins2 protein, mouse) 0 (Insulin) 0 (Interleukin-6) 0 (NFATC Transcription Factors) 0 (Pyrazoles) 0 (Spp1 protein, mouse) 0 (Vasodilator Agents) 0 (interleukin-6, mouse) 0 (transcription factor NF-AT c3) 106441-73-0 (Osteopontin) 169D1260KM (Nitroprusside) EC 1.14.13.39 (Nitric Oxide Synthase Type III) EC 1.14.13.39 (Nos3 protein, mouse) N9YNS0M02X (Acetylcholine) V55S2QJN2X (NG-Nitroarginine Methyl Ester) |
| تواريخ الأحداث: | Date Created: 20191207 Date Completed: 20200803 Latest Revision: 20210110 |
| رمز التحديث: | 20221213 |
| DOI: | 10.2337/db18-0870 |
| PMID: | 31806622 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1939-327X |
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| DOI: | 10.2337/db18-0870 |