Cardiovascular research · 2019
The polarity protein Scrib limits atherosclerosis development in mice.
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Schürmann Christoph, Dienst Franziska L, Pálfi Katalin, Vasconez Andrea E, Oo James A, Wang ShengPeng, Buchmann Giulia K, Offermanns Stefan, van de Sluis Bart, Leisegang Matthias S, Günther Stefan, Humbert Patrick O, Lee Eunjee, Zhu Jun, Weigert Andreas, Mathoor Praveen, Wittig Ilka, Kruse Christoph, Brandes Ralf P
Аннотация
AIMS: The protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized; however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions.
METHODS AND RESULTS: Tamoxifen-induced Scrib-knockout mice were crossed with ApoE-/- knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes.
CONCLUSIONS: By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.
METHODS AND RESULTS: Tamoxifen-induced Scrib-knockout mice were crossed with ApoE-/- knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes.
CONCLUSIONS: By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.
Предметные рубрики MeSH
AnimalsAtherosclerosisCapillary PermeabilityCell AdhesionCell MovementCell PolarityDisease Models, AnimalEndothelial CellsEndothelium, VascularHuman Umbilical Vein Endothelial CellsHumansIntracellular Signaling Peptides and ProteinsMacrophagesMaleMembrane ProteinsMice, Inbred C57BLMice, Knockout, ApoEPhenotypePhosphorylationProto-Oncogene Proteins c-aktRho Guanine Nucleotide Exchange FactorsSignal TransductionTranscriptomeTumor Suppressor ProteinsVasodilation