title: Augmented EGF receptor tyrosine kinase activity impairs vascular function by NADPH oxidase-dependent mechanism in type 2 diabetic mouse.
abstract: We previously determined that augmented EGFR tyrosine kinase (EGFRtk) impairs vascular function in type 2 diabetic mouse (TD2). Here we determined that EGFRtk causes vascular dysfunction through NADPH oxidase activity in TD2. Mesenteric resistance arteries (MRA) from C57/BL6 and db-/db- mice were mounted in a wired myograph and pre-incubated for 1h with either EGFRtk inhibitor (AG1478) or exogenous EGF. The inhibition of EGFRtk did not affect the contractile response to phenylephrine-(PE) and thromboxane-(U46619) or endothelium-dependent relaxation (EDR) to acetylcholine in MRA from control group. However, in TD2 mice, AG1478 reduced the contractile response to U46619, improved vasodilatation and reduced p22phox-NADPH expression, but had no effect on the contractile response to PE. The incubation of MRA with exogenous EGF potentiated the contractile response to PE in MRA from control and diabetic mice. However, EGF impaired the EDR and potentiated the vasoconstriction to U46619 only in the control group. Interestingly, NADPH oxidase inhibition in the presence of EGF restored the normal contraction to PE and improved the EDR but had no effect on the potentiated contraction to U46619. Vascular function improvement was associated with the rescue of eNOS and Akt and reduction in phosphorylated Rho-kinase, NOX4 mRNA levels, and NADPH oxidase activity. MRA from p47phox-/- mice incubated with EGF potentiated the contraction to U46619 but had no effect to PE or ACh responses. The present study provides evidence that augmented EGFRtk impairs vascular function by NADPH oxidase-dependent mechanism. Therefore, EGFRtk and oxidative stress should be potential targets to treat vascular dysfunction in TD2.
authors.affiliation: Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA.
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA.
authors.forename: Karima
authors.initials: K
authors.lastname: Ait-Aissa
authors.affiliation: Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA; College of Nanoscale Science and Engineering, SUNY, Albany, NY 12203, USA.
authors.forename: Maha
authors.initials: M
authors.lastname: Ali
authors.affiliation: Assiut University, Department of Medical Biochemistry, Faculty of Medicine, Assiut, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.affiliation: Department of Physiological Sciences, Eastern Virginia School of Medicine, Norfolk, VA 23501, USA. Electronic address: matrouk@evms.edu.
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003925:Diabetic Angiopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: D003573:Cytochrome b Group; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D010656:Phenylephrine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: EGF; ER stress; Oxidative stress; Type 2 diabetes; Vascular dysfunction