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Atherosclerosis. 2019 Feb 28;284:18-23. doi: 10.1016/j.atherosclerosis.2019.02.020. [Epub ahead of print]

Identification of novel serum markers for the progression of coronary atherosclerosis in WHHLMI rabbits, an animal model of familial hypercholesterolemia.

Author information

1
Institute for Experimental Animals, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Comparative Pathophysiology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: ieakusm@med.kobe-u.ac.jp.
2
Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
3
Division of Evidence-based Laboratory Medicine, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.
4
Division of Comparative Pathophysiology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
5
Institute for Experimental Animals, Kobe University Graduate School of Medicine, Kobe, Japan.
6
University of Michigan Medical Center, Ann Arbor, MI, USA.
7
Division of Metabolomics Research, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
8
Division of Epidemiology, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan.
9
Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Abstract

BACKGROUND AND AIMS:

The development of serum markers specific for coronary lesions is important to prevent coronary events. However, analyses of serum markers in humans are affected by environmental factors and non-target diseases. Using an appropriate model animal can reduce these effects. To identify specific markers for coronary atherosclerosis, we comprehensively analyzed the serum of WHHLMI rabbits, which spontaneously develop coronary atherosclerosis.

METHODS:

Female WHHLMI rabbits were fed standard chow. Serum and plasma were collected under fasting at intervals of 4 months from 4 months old, and a total of 313 lipid molecules, 59 metabolites, lipoprotein lipid levels, and various plasma biochemical parameters were analyzed. The severity of coronary lesions was evaluated with cross-sectional narrowing (CSN) corrected with a frequency of 75%-89% CSN and CSN> 90%.

RESULTS:

There was a large variation in the severity of coronary lesions in WHHLMI rabbits despite almost no differences in plasma biochemical parameters and aortic lesion area between rabbits with severe and mild coronary lesions. The metabolites and lipid molecules selected as serum markers for coronary atherosclerosis were lysophosphatidylcholine (LPC) 22:4 and diacylglycerol 18:0-18:0 at 4 months old, LPC 20:4 (sn-2), ceramide d18:1-18:2, citric acid plus isocitric acid, and pyroglutamic acid at 8 months old, and phosphatidylethanolamine plasminogen 16:1p-22:2 at 16 months old.

CONCLUSIONS:

These serum markers were coronary lesion-specific markers independent of cholesterol levels and aortic lesions and may be useful to detect patients who develop cardiovascular disease.

KEYWORDS:

Coronary atherosclerosis; Lipidome analysis; Metabolome analysis; Serum marker; WHHLMI rabbit

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