title: Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis.
abstract: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.
  
  
  
  Wound healing assays were performed in VSMCs bearing IR (IRLoxP+/+VSMCs), or not (IR-/-VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE-/-mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.
  
  
  
  IGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE-/-mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.
  
  
  
  Our data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Beneit
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain.
authors.forename: C E
authors.initials: CE
authors.lastname: Fernández-García
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Martín-Ventura
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Perdomo
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: Ó
authors.initials: Ó
authors.lastname: Escribano
authors.affiliation: Inserm, U698, Universite Paris 7, CHU X-Bichat, Paris, France.
authors.forename: J B
authors.initials: JB
authors.lastname: Michel
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: García-Gómez
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Fernández
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Díaz-Castroverde
authors.affiliation: CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.|Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Egido
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain. algomezh@ucm.es.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain. algomezh@ucm.es.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain. algomezh@ucm.es.
authors.forename: A
authors.initials: A
authors.lastname: Gómez-Hernández
authors.affiliation: Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.|Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Benito
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D066273:Diet, Western; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D020239:Receptor Cross-Talk / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D001057:Apolipoproteins E; C000597236:IGF1R protein, human; D007328:Insulin; D020033:Protein Isoforms; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Atherosclerosis; Insulin receptor; Migration; Vascular smooth muscle cells