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

Jean Sébastien Saulnier-Blache, Rory Wilson, Kristaps Klavins, Delyth Graham, Ioana Alesutan, Gabi Kastenmüller, Rui Wang-Sattler, Jerzy Adamski, Michael Roden, Wolfgang Rathmann, Jochen Seissler, Christine Meisinger, Wolfgang Koenig, Joachim Thiery, Karsten Suhre, Annette Peters, Makuto Kuro-O, Florian Lang, Guido Dallmann, Christian DellesJakob Voelkl, Melanie Waldenberger, Jean Loup Bascands, Julie Klein, Joost P. Schanstra

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)140-147
Number of pages8
JournalAtherosclerosis
Volume276
DOIs
Publication statusPublished - 1 Sep 2018

Fingerprint

Carotid Intima-Media Thickness
Apolipoproteins E
Cardiovascular Diseases
Animal Models
Cardiovascular Models
Animal Disease Models
Lysophosphatidylcholines
Sphingomyelins
Phosphatidylcholines
Metabolomics
Serum
LDL Cholesterol
Linear Models
Mass Spectrometry
Creatinine
Phospholipids
Salts
Glucose

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ldlr / and ApoE / mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease. / Saulnier-Blache, Jean Sébastien; Wilson, Rory; Klavins, Kristaps; Graham, Delyth; Alesutan, Ioana; Kastenmüller, Gabi; Wang-Sattler, Rui; Adamski, Jerzy; Roden, Michael; Rathmann, Wolfgang; Seissler, Jochen; Meisinger, Christine; Koenig, Wolfgang; Thiery, Joachim; Suhre, Karsten; Peters, Annette; Kuro-O, Makuto; Lang, Florian; Dallmann, Guido; Delles, Christian; Voelkl, Jakob; Waldenberger, Melanie; Bascands, Jean Loup; Klein, Julie; Schanstra, Joost P.

In: Atherosclerosis, Vol. 276, 01.09.2018, p. 140-147.

Research output: Contribution to journalArticle

Saulnier-Blache, JS, Wilson, R, Klavins, K, Graham, D, Alesutan, I, Kastenmüller, G, Wang-Sattler, R, Adamski, J, Roden, M, Rathmann, W, Seissler, J, Meisinger, C, Koenig, W, Thiery, J, Suhre, K, Peters, A, Kuro-O, M, Lang, F, Dallmann, G, Delles, C, Voelkl, J, Waldenberger, M, Bascands, JL, Klein, J & Schanstra, JP 2018, 'Ldlr / and ApoE / mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease', Atherosclerosis, vol. 276, pp. 140-147. https://doi.org/10.1016/j.atherosclerosis.2018.07.024
Saulnier-Blache, Jean Sébastien ; Wilson, Rory ; Klavins, Kristaps ; Graham, Delyth ; Alesutan, Ioana ; Kastenmüller, Gabi ; Wang-Sattler, Rui ; Adamski, Jerzy ; Roden, Michael ; Rathmann, Wolfgang ; Seissler, Jochen ; Meisinger, Christine ; Koenig, Wolfgang ; Thiery, Joachim ; Suhre, Karsten ; Peters, Annette ; Kuro-O, Makuto ; Lang, Florian ; Dallmann, Guido ; Delles, Christian ; Voelkl, Jakob ; Waldenberger, Melanie ; Bascands, Jean Loup ; Klein, Julie ; Schanstra, Joost P. / Ldlr / and ApoE / mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease. In: Atherosclerosis. 2018 ; Vol. 276. pp. 140-147.
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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.",
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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.

PY - 2018/9/1

Y1 - 2018/9/1

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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