title: Implication of insulin receptor A isoform and IRA/IGF-IR hybrid receptors in the aortic vascular smooth muscle cell proliferation: role of TNF-α and IGF-II.
abstract: To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR(-/-) VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-α induced in a ligand-dependent manner a higher association between IRA and TNF-α receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-α induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-α treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-α or IGF-II, which might be of significance in the early atherosclerotic process.
authors.affiliation: Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Instituto de Investigaciones Sanitarias Hospital Clínico San Carlos, Centro de Investigación Biomédica en Red of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid 28040, Spain. almudenagomez@farm.ucm.es
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Hernández
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Escribano
authors.forename: Liliana
authors.initials: L
authors.lastname: Perdomo
authors.forename: Yolanda F
authors.initials: YF
authors.lastname: Otero
authors.forename: Gema
authors.initials: G
authors.lastname: García-Gómez
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández
authors.forename: Nuria
authors.initials: N
authors.lastname: Beneit
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047468:Immunoprecipitation; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin