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Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN, and SYNM.
Perisic Matic, Ljubica; Rykaczewska, Urszula; Razuvaev, Anton; Sabater-Lleal, Maria; Lengquist, Mariette; Miller, Clint L; Ericsson, Ida; Röhl, Samuel; Kronqvist, Malin; Aldi, Silvia; Magné, Joelle; Paloschi, Valentina; Vesterlund, Mattias; Li, Yuhuang; Jin, Hong; Diez, Maria Gonzalez; Roy, Joy; Baldassarre, Damiano; Veglia, Fabrizio; Humphries, Steve E; de Faire, Ulf; Tremoli, Elena; Odeberg, Jacob; Vukojevic, Vladana; Lehtiö, Janne; Maegdefessel, Lars; Ehrenborg, Ewa; Paulsson-Berne, Gabrielle; Hansson, Göran K; Lindeman, Jan H N; Eriksson, Per; Quertermous, Thomas; Hamsten, Anders; Hedin, Ulf.
Afiliación
  • Perisic Matic L; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Rykaczewska U; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Razuvaev A; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Sabater-Lleal M; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Lengquist M; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Miller CL; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Ericsson I; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Röhl S; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Kronqvist M; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Aldi S; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Magné J; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Paloschi V; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Vesterlund M; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Li Y; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Jin H; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Diez MG; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Roy J; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Baldassarre D; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Veglia F; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Humphries SE; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • de Faire U; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Tremoli E; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Odeberg J; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Vukojevic V; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Lehtiö J; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Maegdefessel L; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Ehrenborg E; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Paulsson-Berne G; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Hansson GK; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Lindeman JH; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Eriksson P; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Quertermous T; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Hamsten A; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
  • Hedin U; From the Departments of Molecular Medicine and Surgery (L.P.M., U.R., A.R., M.L., I.E., S.R., M.K., S.A., J.R., U.H.), Medicine (M.S.-L., J.M., V.P., Y.L., H.J., M.G.D., L.M., E.E., G.P.-B., G.K.H., P.E., A.H.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine (U.d.F.), a
Arterioscler Thromb Vasc Biol ; 36(9): 1947-61, 2016 09.
Article en En | MEDLINE | ID: mdl-27470516
ABSTRACT

OBJECTIVE:

Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. APPROACH AND

RESULTS:

Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation.

CONCLUSIONS:

We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo; Autoantígenos/metabolismo; Proteínas de Unión al Calcio/metabolismo; Enfermedades de las Arterias Carótidas/metabolismo; Proteínas del Citoesqueleto/metabolismo; Proteínas de Filamentos Intermediarios/metabolismo; Proteínas con Dominio LIM/metabolismo; Proteínas de Microfilamentos/metabolismo; Músculo Liso Vascular/metabolismo; Miocitos del Músculo Liso/metabolismo; Placa Aterosclerótica; Citoesqueleto de Actina/metabolismo; Proteínas Adaptadoras Transductoras de Señales/genética; Animales; Apolipoproteínas E/deficiencia; Apolipoproteínas E/genética; Aterosclerosis/genética; Aterosclerosis/metabolismo; Aterosclerosis/patología; Autoantígenos/genética; Proteínas de Unión al Calcio/genética; Arterias Carótidas/metabolismo; Arterias Carótidas/patología; Arterias Carótidas/fisiopatología; Enfermedades de las Arterias Carótidas/genética; Enfermedades de las Arterias Carótidas/patología; Enfermedades de las Arterias Carótidas/fisiopatología; Traumatismos de las Arterias Carótidas/genética; Traumatismos de las Arterias Carótidas/metabolismo; Estudios de Casos y Controles; Desdiferenciación Celular; Células Cultivadas; Proteínas del Citoesqueleto/genética; Modelos Animales de Enfermedad; Regulación hacia Abajo; Estudios de Asociación Genética; Humanos; Proteínas de Filamentos Intermediarios/genética; Proteínas con Dominio LIM/genética; Masculino; Ratones Noqueados; Proteínas de Microfilamentos/genética; Persona de Mediana Edad; Músculo Liso Vascular/patología; Músculo Liso Vascular/fisiopatología; Miocitos del Músculo Liso/patología; Neointima; Fenotipo; Interferencia de ARN; Ratas Sprague-Dawley; Transducción de Señal; Factores de Tiempo; Transfección; Vasoconstricción
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Autoantígenos / Proteínas de Unión al Calcio / Enfermedades de las Arterias Carótidas / Proteínas del Citoesqueleto / Miocitos del Músculo Liso / Proteínas Adaptadoras Transductoras de Señales / Placa Aterosclerótica / Proteínas con Dominio LIM / Proteínas de Filamentos Intermediarios / Proteínas de Microfilamentos Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Autoantígenos / Proteínas de Unión al Calcio / Enfermedades de las Arterias Carótidas / Proteínas del Citoesqueleto / Miocitos del Músculo Liso / Proteínas Adaptadoras Transductoras de Señales / Placa Aterosclerótica / Proteínas con Dominio LIM / Proteínas de Filamentos Intermediarios / Proteínas de Microfilamentos Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2016 Tipo del documento: Article