Over-expression of neuron-derived orphan receptor-1 (NOR-1) exacerbates neointimal hyperplasia after vascular injury

Rodríguez-Calvo, R. ; Guadall, A. ; Calvayrac, O. ; Navarro, M. A. (Universidad de Zaragoza) ; Alonso, J. ; Ferrán, B. ; De Diego, A. ; Muniesa, P. (Universidad de Zaragoza) ; Osada, J. (Universidad de Zaragoza) ; Rodríguez, C. ; Martínez-González, J.

Resumen: We have previously shown that NOR-1 (NR4A3) modulates the proliferation and survival of vascular cells in culture. However, in genetically modified animal models, somewhat conflicting results have been reported concerning the involvement of NOR-1 in neointimal formation after vascular injury. The aim of this study was to generate a transgenic mouse model over-expressing NOR-1 in smooth muscle cells (SMCs) and assess the consequence of a gain of function of this receptor on intimal hyperplasia after vascular injury. The transgene construct (SM22-NOR1) was prepared by ligating the full-length human NOR-1 cDNA (hNOR-1) and a mouse SM22a minimal promoter able to drive NOR-1 expression to SMC. Two founders were generated and two stable transgenic mouse lines (TgNOR-1) were established by backcrossing the transgene-carrying founders with C57BL/6J mice. Real-time PCR and immunohistochemistry confirmed that hNOR-1 was mainly targeted to vascular beds such as aorta and carotid arteries, and was similar in both transgenic lines. Vascular SMC from transgenic animals exhibit increased NOR-1 transcriptional activity (assessed by electrophoretic mobility shift assay and luciferase assays), increased mitogenic activity (deter- mined by [3H]-thymidine incorporation; 1.58-fold induction, P < 0.001) and increased expression of embryonic smooth muscle myosin heavy chain (SMemb) than wild-type cells from control littermates. Using the carotid artery ligation model, we show that neointima formation was increased in transgenic versus wild-type mice (2.36-fold induction, P < 0.01). Our in vivo data support a role for NOR-1 in VSMC proliferation and vascular remodelling. This NOR-1 transgenic mouse could be a useful model to study fibroproliferative vascular diseases.

Idioma: Inglés

DOI: 10.1093/hmg/ddt042

Año: 2013

Publicado en: HUMAN MOLECULAR GENETICS 22, 10 (2013), 1949-1959
ISSN: 0964-6906

Factor impacto JCR: 6.677 (2013)

Categ. JCR: GENETICS & HEREDITY rank: 16 / 164 = 0.098 (2013) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 32 / 290 = 0.11 (2013) - Q1 - T1

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0053
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2009-11949
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2012-40127
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PI12-01952

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Área Anatom.Anatom.Patológ.Com (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)