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Atherosclerosis. 2018 Sep;276:140-147. doi: 10.1016/j.atherosclerosis.2018.07.024. Epub 2018 Jul 21.

Ldlr-/- and ApoE-/- mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease.

Author information

1
Institute of Cardiovascular and Metabolic Disease, Institut National de La Santé et de La Recherche Médicale (INSERM), Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France. Electronic address: jean-sebastien.saulnier-blache@inserm.fr.
2
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany.
3
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
4
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
5
Medizinische Klinik Mit Schwerpunkt Kardiologie, Campus Virchow-Klinikum, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
6
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
7
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany.
8
Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
9
German Diabetes Center, Leibniz Institute at Heinrich Heine University Düsseldorf, Institute of Biometrics and Epidemiology, Düsseldorf, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
10
Diabetes Zentrum, Medizinische Klinik und Poliklinik IV - Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany; Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universität München and Helmholtz Zentrum München, Munich, Germany.
11
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T, Augsburg, Germany.
12
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
13
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany.
14
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO Box 24144, Doha, Qatar.
15
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany; Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.
16
Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
17
Physiologisches Institut, University of Tübingen, 72076 Tübingen, Germany; Department of Molecular Medicine II, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
18
Biocrates Life Sciences AG, Eduard-Bodem-Gasse 8, 6020 Innsbruck, Austria; Department of Molecular Medicine II, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
19
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
20
Institut National de La Sante et de La Recherche Médicale (INSERM), U1188 - Université de La Réunion, France.
21
Institute of Cardiovascular and Metabolic Disease, Institut National de La Santé et de La Recherche Médicale (INSERM), Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.

Abstract

BACKGROUND AND AIMS:

Preclinical experiments on animal models are essential to understand the mechanisms of cardiovascular disease (CVD). Metabolomics allows access to the metabolic perturbations associated with CVD in heart and vessels. Here we assessed which potential animal CVD model most closely mimics the serum metabolite signature of increased carotid intima-media thickness (cIMT) in humans, a clinical parameter widely accepted as a surrogate of CVD.

METHODS:

A targeted mass spectrometry assay was used to quantify and compare a series of blood metabolites between 1362 individuals (KORA F4 cohort) and 5 animal CVD models: ApoE-/-, Ldlr-/-, and klotho-hypomorphic mice (kl/kl) and SHRSP rats with or without salt feeding. The metabolite signatures were obtained using linear regressions adjusted for various co-variates.

RESULTS:

In human, increased cIMT [quartile Q4 vs. Q1] was associated with 26 metabolites (9 acylcarnitines, 2 lysophosphatidylcholines, 9 phosphatidylcholines and 6 sphingomyelins). Acylcarnitines correlated preferentially with serum glucose and creatinine. Phospholipids correlated preferentially with cholesterol (total and LDL). The human signature correlated positively and significantly with Ldlr-/- and ApoE-/- mice, while correlation with kl/kl mice and SHRP rats was either negative and non-significant. Human and Ldlr-/- mice shared 11 significant metabolites displaying the same direction of regulation: 5 phosphatidylcholines, 1 lysophosphatidylcholines, 5 sphingomyelins; ApoE-/- mice shared 10.

CONCLUSIONS:

The human cIMT signature was partially mimicked by Ldlr-/- and ApoE-/- mice. These animal models might help better understand the biochemical and molecular mechanisms involved in the vessel metabolic perturbations associated with, and contributing to metabolic disorders in CVD.

KEYWORDS:

Acylcarnitines; Animal models; Atherosclerosis; Cardiovascular disease; Carotid intima media thickness; Metabolomics; Phospholipids

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