Proteomics based identification of KDM5 histone demethylases associated with cardiovascular disease
| Autor: | William Mullen, Jean-Loup Bascands, Burkert Pieske, Jean Sébastien Saulnier-Blache, Julie Klein, Joost P. Schanstra, Maria G. Roubelakis, Vasiliki Bitsika, Antonia Vlahou, Marika Mokou, Jerome Zoidakis, Harald Mischak, Manousos Makridakis, Michael Sacherer |
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| Přispěvatelé: | University of Athens Medical School [Athens], Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), University of Glasgow, University of Graz, Berlin Institute of Health (BIH), Saulnier-Blache, Jean Sébastien, Biomedical Research Foundation of the Academy of Athens, Université Fédérale Toulouse Midi-Pyrénées, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karl-Franzens-Universität Graz, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Mosaiques Diagnostics GmbH, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Karl-Franzens-Universität [Graz, Autriche] |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Male Proteomics Research paper Angiogenesis Diabetic Cardiomyopathies [SDV]Life Sciences [q-bio] Biology General Biochemistry Genetics and Molecular Biology Mass Spectrometry H3K4 Minor Histocompatibility Antigens 03 medical and health sciences Histone H3 Mice 0302 clinical medicine Human Umbilical Vein Endothelial Cells Animals Humans KDM5 Histone Demethylases Diabetes Proteins General Medicine Atherosclerosis Cardiovascular disease 3. Good health Mice Inbred C57BL [SDV] Life Sciences [q-bio] 030104 developmental biology 030220 oncology & carcinogenesis Proteome biology.protein Cancer research H3K4me3 Demethylase |
| Zdroj: | EBioMedicine EBioMedicine, Elsevier, 2019, 41, pp.91-104. ⟨10.1016/j.ebiom.2019.02.040⟩ EBioMedicine, 2019, 41, pp.91-104. ⟨10.1016/j.ebiom.2019.02.040⟩ |
| ISSN: | 2352-3964 |
| Popis: | 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]. |
| Databáze: | OpenAIRE |
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