Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context
Background: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. Methods: LC-MS/MS analysis of thoracic a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419301185 |
| _version_ | 1828155014824067072 |
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| author | Marika Mokou Julie Klein Manousos Makridakis Vasiliki Bitsika Jean-Loup Bascands Jean Sebastien Saulnier-Blache William Mullen Michael Sacherer Jerome Zoidakis Burkert Pieske Harald Mischak Maria G. Roubelakis Joost P. Schanstra Antonia Vlahou |
| author_facet | Marika Mokou Julie Klein Manousos Makridakis Vasiliki Bitsika Jean-Loup Bascands Jean Sebastien Saulnier-Blache William Mullen Michael Sacherer Jerome Zoidakis Burkert Pieske Harald Mischak Maria G. Roubelakis Joost P. Schanstra Antonia Vlahou |
| author_sort | Marika Mokou |
| collection | DOAJ |
| description | Background: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. Methods: LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells. Findings: Comparative tissue proteomics of low density lipoprotein receptor deficient (Ldlr−/−) and diabetic Ldlr−/− (Ldlr−/−STZ) with wild type (WT) animals led to the identification of 284 differentially expressed proteins in both models. Among them, 177 proteins were also differentially expressed in diabetic apolipoprotein E deficient (ApoE−/−STZ) mice, suggesting expression changes associated with atherosclerosis independent of the model used. These proteins recapitulated the hallmarks of atherosclerosis. Comparison of these findings with differentially expressed proteins in human vessels with CVD enabled shortlisting of six commonly dysregulated proteins. Among them, lysine-specific demethylase 5D (KDM5D) exhibited pronounced overexpression accompanied by a reduction in the protein levels of its substrate, the trimethylated lysine 4 of histone H3 (H3K4me3), in patients with CVD. Functional interference studies applying a KDM5 inhibitor on HUVEC reduced cell proliferation, migration and tube-forming ability in vitro. Interpretation: This high-throughput proteomics strategy identified KDM5 histone demethylases being potentially involved in CVD, possibly by affecting H3K4 methylation. Fund: [SysVasc, HEALTH-2013 603288], [ERA-CVD PROACT: ANR-17-ECVD-0006, 01KL1805], [FRM, DEQ20170336759]. Keywords: Cardiovascular disease, Atherosclerosis, Diabetes, Proteomics, KDM5, H3K4 |
| first_indexed | 2024-04-11T22:47:17Z |
| format | Article |
| id | doaj.art-839a068c0692417e930ff08a97b6c677 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-11T22:47:17Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-839a068c0692417e930ff08a97b6c6772022-12-22T03:58:43ZengElsevierEBioMedicine2352-39642019-03-014191104Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in contextMarika Mokou0Julie Klein1Manousos Makridakis2Vasiliki Bitsika3Jean-Loup Bascands4Jean Sebastien Saulnier-Blache5William Mullen6Michael Sacherer7Jerome Zoidakis8Burkert Pieske9Harald Mischak10Maria G. Roubelakis11Joost P. Schanstra12Antonia Vlahou13Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Biology, University of Athens, School of Medicine, Athens, GreeceInstitut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier Toulouse, Toulouse, FranceBiotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceBiotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceINSERM, U1188, Sainte Clotilde, La Réunion, France; Université de La Réunion, Sainte Clotilde, La Réunion, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier Toulouse, Toulouse, FranceBHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United KingdomDepartment of Cardiology, Medical University of Graz, Graz, AustriaBiotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, GreeceDepartment of Internal Medicine and Cardiology, Charité University Medicine, Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany; Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany; Berlin Institute of Health (BIH), GermanyBHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Mosaiques Diagnostics GmbH, Hannover, GermanyLaboratory of Biology, University of Athens, School of Medicine, Athens, GreeceInstitut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France; Correspondence to: J. P. Schanstra, INSERM, Unit 1048, 1 Avenue J. Poulhes, 31432 Toulouse, France.Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Correspondence to: A. Vlahou, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou St., 115 27 Athens, Greece.Background: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. Methods: LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells. Findings: Comparative tissue proteomics of low density lipoprotein receptor deficient (Ldlr−/−) and diabetic Ldlr−/− (Ldlr−/−STZ) with wild type (WT) animals led to the identification of 284 differentially expressed proteins in both models. Among them, 177 proteins were also differentially expressed in diabetic apolipoprotein E deficient (ApoE−/−STZ) mice, suggesting expression changes associated with atherosclerosis independent of the model used. These proteins recapitulated the hallmarks of atherosclerosis. Comparison of these findings with differentially expressed proteins in human vessels with CVD enabled shortlisting of six commonly dysregulated proteins. Among them, lysine-specific demethylase 5D (KDM5D) exhibited pronounced overexpression accompanied by a reduction in the protein levels of its substrate, the trimethylated lysine 4 of histone H3 (H3K4me3), in patients with CVD. Functional interference studies applying a KDM5 inhibitor on HUVEC reduced cell proliferation, migration and tube-forming ability in vitro. Interpretation: This high-throughput proteomics strategy identified KDM5 histone demethylases being potentially involved in CVD, possibly by affecting H3K4 methylation. Fund: [SysVasc, HEALTH-2013 603288], [ERA-CVD PROACT: ANR-17-ECVD-0006, 01KL1805], [FRM, DEQ20170336759]. Keywords: Cardiovascular disease, Atherosclerosis, Diabetes, Proteomics, KDM5, H3K4http://www.sciencedirect.com/science/article/pii/S2352396419301185 |
| spellingShingle | Marika Mokou Julie Klein Manousos Makridakis Vasiliki Bitsika Jean-Loup Bascands Jean Sebastien Saulnier-Blache William Mullen Michael Sacherer Jerome Zoidakis Burkert Pieske Harald Mischak Maria G. Roubelakis Joost P. Schanstra Antonia Vlahou Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context EBioMedicine |
| title | Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context |
| title_full | Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context |
| title_fullStr | Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context |
| title_full_unstemmed | Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context |
| title_short | Proteomics based identification of KDM5 histone demethylases associated with cardiovascular diseaseResearch in context |
| title_sort | proteomics based identification of kdm5 histone demethylases associated with cardiovascular diseaseresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419301185 |
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