Frank Spillmann1, Kapka Miteva1, Burkert Pieske1, Carsten Tschöpe1, Sophie Van Linthout2. 1. From the Department of Cardiology (F.S., B.P., C.T.) and Berlin-Brandenburg Center for Regenerative Therapy (BCRT) (K.M., C.T., S.V.L.), Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany; Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany (B.P.); and Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Germany (B.P., C.T., S.V.L.). 2. From the Department of Cardiology (F.S., B.P., C.T.) and Berlin-Brandenburg Center for Regenerative Therapy (BCRT) (K.M., C.T., S.V.L.), Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany; Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany (B.P.); and Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Germany (B.P., C.T., S.V.L.). sophie.van-linthout@charite.de.
Abstract
OBJECTIVE: Endothelial-to-mesenchymal transition is an inflammation-induced process by which endothelial cells can transdifferentiate into fibroblasts. Based on the endothelial-protective and antifibrotic effects of high-density lipoproteins (HDL), we aimed to investigate whether HDL can reduce endothelial-to-mesenchymal transition. APPROACH AND RESULTS: Therefore, human aortic endothelial cells were stimulated with the profibrotic factor transforming growth factor (TGF)-β1 in the presence or absence of HDL. Their impact on the transition of endothelial cells to mesenchymal-like cells was analyzed. Phase contrast microscopy demonstrated that HDL abrogated the TGF-β1-induced spindle-shape morphology in human aortic endothelial cells. Furthermore, HDL decreased the TGF-β1-mediated induction of α-smooth muscle actin expression and concomitant loss in endothelial cadherin expression, as shown by immunofluorescence staining and flow cytometry. In addition, HDL decreased the TGF-β1-induced collagen deposition in human aortic endothelial cells involving the scavenger receptor class B, type 1 and downstream phosphatidyl inositol-3-kinase following the findings that the HDL-mediated reduction was abrogated by scavenger receptor class B, type 1 siRNA knockdown and phosphatidyl inositol-3-kinase inhibition, respectively. The HDL-mediated reduction in endothelial-to-mesenchymal transition was associated with an induction of the inhibitory Smad, Smad 7. CONCLUSIONS: We provide the first in vitro evidence that the endothelial-protective and antifibrotic effects of HDL include the reduction in endothelial-to-mesenchymal transition.
OBJECTIVE: Endothelial-to-mesenchymal transition is an inflammation-induced process by which endothelial cells can transdifferentiate into fibroblasts. Based on the endothelial-protective and antifibrotic effects of high-density lipoproteins (HDL), we aimed to investigate whether HDL can reduce endothelial-to-mesenchymal transition. APPROACH AND RESULTS: Therefore, human aortic endothelial cells were stimulated with the profibrotic factor transforming growth factor (TGF)-β1 in the presence or absence of HDL. Their impact on the transition of endothelial cells to mesenchymal-like cells was analyzed. Phase contrast microscopy demonstrated that HDL abrogated the TGF-β1-induced spindle-shape morphology in human aortic endothelial cells. Furthermore, HDL decreased the TGF-β1-mediated induction of α-smooth muscle actin expression and concomitant loss in endothelial cadherin expression, as shown by immunofluorescence staining and flow cytometry. In addition, HDL decreased the TGF-β1-induced collagen deposition in human aortic endothelial cells involving the scavenger receptor class B, type 1 and downstream phosphatidyl inositol-3-kinase following the findings that the HDL-mediated reduction was abrogated by scavenger receptor class B, type 1 siRNA knockdown and phosphatidyl inositol-3-kinase inhibition, respectively. The HDL-mediated reduction in endothelial-to-mesenchymal transition was associated with an induction of the inhibitory Smad, Smad 7. CONCLUSIONS: We provide the first in vitro evidence that the endothelial-protective and antifibrotic effects of HDL include the reduction in endothelial-to-mesenchymal transition.
Authors: Jason C Kovacic; Stefanie Dimmeler; Richard P Harvey; Toren Finkel; Elena Aikawa; Guido Krenning; Andrew H Baker Journal: J Am Coll Cardiol Date: 2019-01-22 Impact factor: 24.094
Authors: Kapka Miteva; Sophie Van Linthout; Kathleen Pappritz; Irene Müller; Frank Spillmann; Marion Haag; Harald Stachelscheid; Jochen Ringe; Michael Sittinger; Carsten Tschöpe Journal: Stem Cells Transl Med Date: 2016-07-26 Impact factor: 6.940