| Chronic inhibition of epidermal growth factor receptor tyrosine kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2) augments vascular response to limb ischemia in type 2 diabetic mice. | |
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MedLine Citation:
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PMID: 22067908 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Type 2 diabetes is a key risk factor for ischemia-dependent pathology; therefore, a significant medical need exists to develop novel therapies that increase the formation of new vessels. We explored the therapeutic potential of epidermal growth factor receptor tyrosine kinase (EGFRtk) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibition in impaired ischemia-induced neovascularization in type 2 diabetes. Unilateral femoral artery ligation was performed in diabetic (db(-)/db(-)) and their control (db(-)/db(+)) mice for 4 weeks, followed by treatments with EGFRtk and ERK1/2 inhibitors (AG1478, 10 mg/kg/day and U0126, 400 μg/kg/day, respectively) for 3 weeks. Neovascularization, blood flow recovery, vascular and capillary density, and endothelial nitric oxide synthase activity were significantly impaired and were associated with enhanced EGFRtk and ERK1/2 activity in db(-)/db(-) mice. EGFRtk and ERK1/2 inhibitors did not have any effect in control mice, while in db(-)/db(-) mice there was a significant increase in neovascularization, blood flow recovery, vascular and capillary density, endothelial nitric oxide synthase activity, and were associated with a decrease in EGFRtk and ERK1/2 activity. Our data demonstrated that the inhibition of EGFRtk and ERK1/2 restored ischemia-induced neovascularization and blood flow recovery in type 2 diabetic mice. Thus, EGFRtk and ERK1/2 could be possible targets to protect from ischemia-induced vascular pathology in type 2 diabetes. |
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Authors:
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Soo-Kyoung Choi; Maria Galán; Megan Partyka; Mohamed Trebak; Souad Belmadani; Khalid Matrougui |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-11-07 |
Journal Detail:
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Title: The American journal of pathology Volume: 180 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2011-12-19 Completed Date: 2012-02-17 Revised Date: 2012-05-01 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 410-8 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana 70112, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Flow Velocity / physiology Blood Glucose / metabolism Body Weight / physiology Capillaries / physiology Cyclic GMP / metabolism Diabetes Mellitus, Type 2 / blood, physiopathology, prevention & control* Diabetic Angiopathies / blood, physiopathology, prevention & control* Hindlimb / blood supply* Insulin / metabolism Ischemia / blood, physiopathology, prevention & control* Male Mice Nitric Oxide Synthase Type III / metabolism Phosphorylation RNA, Messenger / metabolism Receptor Protein-Tyrosine Kinases / antagonists & inhibitors* Receptor, Epidermal Growth Factor / antagonists & inhibitors* Vascular Endothelial Growth Factor A / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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1R01HL095566/HL/NHLBI NIH HHS; 5R01HL097111/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 0/Insulin; 0/RNA, Messenger; 0/Vascular Endothelial Growth Factor A; 7665-99-8/Cyclic GMP; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, Epidermal Growth Factor |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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