TY - JOUR
T1 - Ldlr− / − and ApoE− / − mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease
AU - Saulnier-Blache, Jean Sébastien
AU - Wilson, Rory
AU - Klavins, Kristaps
AU - Graham, Delyth
AU - Alesutan, Ioana
AU - Kastenmüller, Gabi
AU - Wang-Sattler, Rui
AU - Adamski, Jerzy
AU - Roden, Michael
AU - Rathmann, Wolfgang
AU - Seissler, Jochen
AU - Meisinger, Christine
AU - Koenig, Wolfgang
AU - Thiery, Joachim
AU - Suhre, Karsten
AU - Peters, Annette
AU - Kuro-O, Makuto
AU - Lang, Florian
AU - Dallmann, Guido
AU - Delles, Christian
AU - Voelkl, Jakob
AU - Waldenberger, Melanie
AU - Bascands, Jean Loup
AU - Klein, Julie
AU - Schanstra, Joost P.
N1 - Funding Information:
The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria . The work was supported by grants from: grant agreement n°603288 (SysVasc) from the European Union Seventh Framework Programme ( FP7/2007–2013 ); the Institut National de Santé et de Recherche Médicale (INSERM) , France; the BHF Centre of Research Excellence Award RE/13/5/30177 .
Funding Information:
The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. The work was supported by grants from: grant agreement n°603288 (SysVasc) from the European Union Seventh Framework Programme (FP7/2007–2013); the Institut National de Santé et de Recherche Médicale (INSERM), France; the BHF Centre of Research Excellence Award RE/13/5/30177.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - Acylcarnitines
KW - Animal models
KW - Atherosclerosis
KW - Cardiovascular disease
KW - Carotid intima media thickness
KW - Metabolomics
KW - Phospholipids
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U2 - 10.1016/j.atherosclerosis.2018.07.024
DO - 10.1016/j.atherosclerosis.2018.07.024
M3 - Article
C2 - 30059845
AN - SCOPUS:85050553718
SN - 0021-9150
VL - 276
SP - 140
EP - 147
JO - Atherosclerosis
JF - Atherosclerosis
ER -