Τίτλος:
Proteomics based identification of KDM5 histone demethylases associated with cardiovascular disease
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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]. © 2019
Συγγραφείς:
Mokou, M.
Klein, J.
Makridakis, M.
Bitsika, V.
Bascands, J.-L.
Saulnier-Blache, J.S.
Mullen, W.
Sacherer, M.
Zoidakis, J.
Pieske, B.
Mischak, H.
Roubelakis, M.G.
Schanstra, J.P.
Vlahou, A.
Λέξεις-κλειδιά:
histone demethylase; histone demethylase KDM5; unclassified drug; histone demethylase; Jarid1d protein, mouse; KDM5D protein, human; minor histocompatibility antigen; protein, adult; angiogenesis; animal experiment; animal model; animal tissue; Article; assay; atherosclerosis; bioinformatics; cardiovascular disease; cell migration; cell proliferation; clinical article; controlled study; diabetes mellitus; endothelium cell; female; flow cytometry; human; human cell; human tissue; liquid chromatography-mass spectrometry; male; middle aged; mouse; MTS assay; nonhuman; polymerase chain reaction; priority journal; protein expression; proteomics; transwell migration assay; tube formation assay; Western blotting; animal; C57BL mouse; diabetic cardiomyopathy; genetics; mass spectrometry; metabolism; proteomics; umbilical vein endothelial cell, Animals; Atherosclerosis; Diabetic Cardiomyopathies; Histone Demethylases; Human Umbilical Vein Endothelial Cells; Humans; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Proteins; Proteomics
DOI:
10.1016/j.ebiom.2019.02.040
