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EBioMedicine. 2019 Feb 27. pii: S2352-3964(19)30118-5. doi: 10.1016/j.ebiom.2019.02.040. [Epub ahead of print]

Proteomics based identification of KDM5 histone demethylases associated with cardiovascular disease.

Author information

1
Biotechnology 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, Greece.
2
Institut 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.
3
Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
4
INSERM, U1188, Sainte Clotilde, La Réunion, France; Université de La Réunion, Sainte Clotilde, La Réunion, France.
5
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
6
Department of Cardiology, Medical University of Graz, Graz, Austria.
7
Department 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), Germany.
8
BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Mosaiques Diagnostics GmbH, Hannover, Germany.
9
Laboratory of Biology, University of Athens, School of Medicine, Athens, Greece.
10
Institut 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. Electronic address: joost-peter.schanstra@inserm.fr.
11
Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: vlahoua@bioacademy.gr.

Abstract

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:

Atherosclerosis; Cardiovascular disease; Diabetes; H3K4; KDM5; Proteomics

PMID:
30826357
DOI:
10.1016/j.ebiom.2019.02.040
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