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

Soo Kyoung Choi, Maria Galán, Megan Partyka, Mohamed Trebak, Souad Belmadani, Khalid Matrougui

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 signalregulated 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.

Original languageEnglish (US)
Pages (from-to)410-418
Number of pages9
JournalAmerican Journal of Pathology
Volume180
Issue number1
DOIs
StatePublished - Jan 1 2012

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Blood Vessels
Ischemia
Extremities
Type 2 Diabetes Mellitus
Nitric Oxide Synthase Type III
Pathology
Femoral Artery
Ligation
Phosphotransferases
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

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title = "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",
abstract = "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 signalregulated 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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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. / Choi, Soo Kyoung; Galán, Maria; Partyka, Megan; Trebak, Mohamed; Belmadani, Souad; Matrougui, Khalid.

In: American Journal of Pathology, Vol. 180, No. 1, 01.01.2012, p. 410-418.

Research output: Contribution to journalArticle

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