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Zebrafish Model for Functional Screening of Flow-Responsive Genes.
Serbanovic-Canic, Jovana; de Luca, Amalia; Warboys, Christina; Ferreira, Pedro F; Luong, Le A; Hsiao, Sarah; Gauci, Ismael; Mahmoud, Marwa; Feng, Shuang; Souilhol, Celine; Bowden, Neil; Ashton, John-Paul; Walczak, Henning; Firmin, David; Krams, Rob; Mason, Justin C; Haskard, Dorian O; Sherwin, Spencer; Ridger, Victoria; Chico, Timothy J A; Evans, Paul C.
Afiliação
  • Serbanovic-Canic J; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • de Luca A; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Warboys C; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Ferreira PF; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Luong LA; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Hsiao S; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Gauci I; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Mahmoud M; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Feng S; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Souilhol C; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Bowden N; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Ashton JP; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Walczak H; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Firmin D; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Krams R; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Mason JC; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Haskard DO; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Sherwin S; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Ridger V; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Chico TJ; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
  • Evans PC; From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), Univ
Arterioscler Thromb Vasc Biol ; 37(1): 130-143, 2017 01.
Article em En | MEDLINE | ID: mdl-27834691
ABSTRACT

OBJECTIVE:

Atherosclerosis is initiated at branches and bends of arteries exposed to disturbed blood flow that generates low shear stress. This mechanical environment promotes lesions by inducing endothelial cell (EC) apoptosis and dysfunction via mechanisms that are incompletely understood. Although transcriptome-based studies have identified multiple shear-responsive genes, most of them have an unknown function. To address this, we investigated whether zebrafish embryos can be used for functional screening of mechanosensitive genes that regulate EC apoptosis in mammalian arteries. APPROACH AND

RESULTS:

First, we demonstrated that flow regulates EC apoptosis in developing zebrafish vasculature. Specifically, suppression of blood flow in zebrafish embryos (by targeting cardiac troponin) enhanced that rate of EC apoptosis (≈10%) compared with controls exposed to flow (≈1%). A panel of candidate regulators of apoptosis were identified by transcriptome profiling of ECs from high and low shear stress regions of the porcine aorta. Genes that displayed the greatest differential expression and possessed 1 to 2 zebrafish orthologues were screened for the regulation of apoptosis in zebrafish vasculature exposed to flow or no-flow conditions using a knockdown approach. A phenotypic change was observed in 4 genes; p53-related protein (PERP) and programmed cell death 2-like protein functioned as positive regulators of apoptosis, whereas angiopoietin-like 4 and cadherin 13 were negative regulators. The regulation of perp, cdh13, angptl4, and pdcd2l by shear stress and the effects of perp and cdh13 on EC apoptosis were confirmed by studies of cultured EC exposed to flow.

CONCLUSIONS:

We conclude that a zebrafish model of flow manipulation coupled to gene knockdown can be used for functional screening of mechanosensitive genes in vascular ECs, thus providing potential therapeutic targets to prevent or treat endothelial injury at atheroprone sites.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peixe-Zebra / Apoptose / Regulação da Expressão Gênica no Desenvolvimento / Proteínas de Peixe-Zebra / Mecanotransdução Celular / Células Endoteliais / Aterosclerose Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals / Female / Humans Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2017 Tipo de documento: Article País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peixe-Zebra / Apoptose / Regulação da Expressão Gênica no Desenvolvimento / Proteínas de Peixe-Zebra / Mecanotransdução Celular / Células Endoteliais / Aterosclerose Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals / Female / Humans Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2017 Tipo de documento: Article País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA