Carolin Lerchenmüller1, Julian Heißenberg2, Federico Damilano2, Vassilios J Bezzeridis2, Isabel Krämer2, Marie-Luce Bochaton-Piallat2, Kristóf Hirschberg2, Martin Busch2, Hugo A Katus2, Karsten Peppel2, Anthony Rosenzweig2, Hauke Busch2, Melanie Boerries1, Patrick Most2. 1. From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries). clerchenmueller@mgh.harvard.edu m.boerries@dkfz.de. 2. From the Cardiovascular Research Center, Massachusetts General Hospital (C.L., F.D., A.R.), Cardiovascular Institute, Beth Israel Deaconess Medical Center (F.D.), and Boston Children's Hospital (V.J.B.), Harvard Medical School, Boston, MA; Molecular and Translational Cardiology (MTC), Department of Internal Medicine III, University Hospital Heidelberg, Germany (C.L., J.H., I.K., M. Busch, P.M.); Department of Pathology and Immunology, University of Geneva, Switzerland (M.-L.B.-P.); DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, University of Heidelberg, Germany (K.H., M. Busch, H.A.K., P.M.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA (K.P., P.M.); Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany (H.B., M. Boerries); German Cancer Consortium (DKTK), Freiburg, Germany (H.B., M. Boerries); and German Cancer Research Center (DKFZ), Heidelberg, Germany (H.B., M. Boerries).
Abstract
OBJECTIVE: S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive. APPROACH AND RESULTS: Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1. CONCLUSIONS: Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.
OBJECTIVE:S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive. APPROACH AND RESULTS: Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1. CONCLUSIONS: Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.
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