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

Shiomi, Masashi; Takeda, Hiroaki; Irino, Yasuhiro; Kimura, N; Yamada, Satoshi; Kuniyoshi, Nobue; Kikumori, Akio; Koike, Yu; Koike, Tomonari; Yoshida, Masaru; Izumi, Yoshihiro; Shinohara, Masakazu; Bamba, Takeshi; Ishida, Tatsuro

doi:10.1016/j.atherosclerosis.2019.02.020

Cited by 11 publications

(19 citation statements)

References 39 publications

(54 reference statements)

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“…akita-u.ac.jp/~doubutu/WHHL/WHHL-home.html). those of aortic lesions 68,75) . Because there were gender differences in the metabolome analysis of 59 metabolites and lipidome analysis of 313 lipid molecules, we analyzed data for females with large coronary artery disease deviations 75) .…”

Section: Resultsmentioning

confidence: 99%

“…those of aortic lesions 68,75) . Because there were gender differences in the metabolome analysis of 59 metabolites and lipidome analysis of 313 lipid molecules, we analyzed data for females with large coronary artery disease deviations 75) . In female WHHLMI rabbits, molecules selected as serum markers for coronary lesions 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, pyroglutamic acid at 8 months old, and phosphatidylethanolamine plasminogen 16:1p-22:2 at 16 months old.…”

Section: Resultsmentioning

confidence: 99%

“…method, but they did not refer to coronary lesions. In our experience, LDL receptor deficiency in WHHL rabbits is responsible for hypercholesterolemia and aortic atherosclerosis, but the progression of coronary atherosclerosis is regulated by unknown factors 75) . There was a great variation in the severity of coronary lesions in the homozygous offspring obtained by cross-breeding the homozygous WHHLMI rabbits with the heterozygotes (unpublished results), despite similar levels of serum lipid levels and aortic lesions.…”

Section: Arterial Lesions Developed In Other Arteriesmentioning

confidence: 96%

“…Therefore, it should be noted that the pathogenesis of ath- Table 3. Characteristics of coronary lesions elucidated in studies using WHHL rabbit family • Differences between coronary artery lesions rich in fibers and aortic lesions rich in lipids 15,61) • The relevance of factors other than conventional risk factors (such as serum total cholesterol levels, HDL levels, oxidative stress, hyperglycemia, hypertension, and others) in the development and progression of coronary lesions 75) • Involvement of genetic factors different from aortic lesions in the development of coronary artery lesions 75) , and involvement of the coronary curvature in the progression and composition of lesions 68) • The relevance of additional factor(s) in the rupture of unstable coronary lesions characterized by thin-capped fibroatheroma 4,22,65) • Involvement of coronary spasm in rupture of coronary lesions and the occurrence of acute coronary syndromes 22,65) • The relevance of several serum lipid molecules identified with lipidome analyses in the development and progression of coronary lesions 75) • Involvement of macrophages infiltrated into the deep area of intima through vasa vasorum 29) in coronary outward remodeling 67) • Suppression and destabilization of atherosclerotic lesions by lowering serum lipid levels 5) human coronary lesions 30) , various types of coronary lesions were observed in WHHLMI rabbits (Fig. 3), such as fatty streak, fibrous lesion, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc.…”

Section: Contribution Of Whhl Rabbits To Studies Of Atherogenesismentioning

confidence: 99%

“…We attempted to identify serum markers for the progression of coronary lesions and/or the development of myocardial infarction in WHHLMI rabbits 75) . Using WHHLMI rabbits has several advantages in studies of identification of serum markers for coronary lesions; 1) it is easy to keep constant several factors, such as dietary habits, environmental conditions, non-target diseases, and social stress; 2) there is no influence of artificial factors that occur when atherosclerotic lesions are induced artificially; 3) coronary lesions and/ or myocardial infarction are developed spontaneously.…”

Section: Genome Analyses Of Whhlmi Rabbits and Identification Of Serumentioning

confidence: 99%

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The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

Shiomi

2020

JAT

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ReviewAnimal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5)The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Arterial Lesions Developed In Other Arteriesmentioning

confidence: 96%

Section: Contribution Of Whhl Rabbits To Studies Of Atherogenesismentioning

confidence: 99%

Section: Genome Analyses Of Whhlmi Rabbits and Identification Of Serumentioning

confidence: 99%

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The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

Shiomi

2020

JAT

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The Monocyte to High‐Density Lipoprotein Cholesterol Ratio in the Prediction for Atherosclerosis: A Retrospective Study in Adult Chinese Participants

Zhou

Wang

Jia

et al. 2020

Lipids

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The ratio of monocyte to high‐density lipoprotein cholesterol level (MHR) was a newly proposed inflammatory and oxidative stress marker. This study aimed to explore the association between MHR and Brachial‐ankle pulse wave velocity (Ba‐PWV) in adult Chinese participants. A total of 2029 participants were divided into two groups according to the Ba‐PWV: a high Ba‐PWV group (Ba‐PWV ≥1400 cm/s) and a low Ba‐PWV group (Ba‐PWV < 1400 cm/s). According to the cut‐off points of quartile of MHR, the participants were divided into four groups. The relationship between MHR and Ba‐PWV was analyzed. After adjusting for potential confounders, a non‐linear relationship between MHR and Ba‐PWV was found in the participants, and the inflection point was 7.78 in the non‐linear curve. On the left of the inflection point, MHR had a positive correlation with Ba‐PWV (OR = 1.17, 95% confidence interval (CI): 1.08 to 1.28, p < 0.01). However, there was no obvious relationship between MHR and Ba‐PWV on the right of the inflection point (OR = 0.96, 95% CI: 0.90 to 1.01, p = 0.117). Further demographic analysis demonstrated that the positive relationship between MHR and Ba‐PWV was found in the female participants with hypertension family history, but without a current history of hypertension, smoking, or drinking (p < 0.05). An increased MHR is a risk factor of atherosclerosis, which may predict the potential development of atherosclerosis. When the MHR is close to 7.78, it has the highest predictive value for the risk of atherosclerosis occurrence.

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Lipid Profiling of Serum and Lipoprotein Fractions in Response to Pitavastatin Using an Animal Model of Familial Hypercholesterolemia

et al. 2020

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Statins are widely used for the treatment of atherosclerotic cardiovascular diseases. They inhibit cholesterol biosynthesis in the liver and cause pleiotropic effects, including anti-inflammatory and antioxidant effects. To develop novel therapeutic drugs, the effect of blood-borne lipid molecules on the pleiotropic effects of statins must be elucidated. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for hypercholesterolemia, are suitable for the determination of lipid molecules in the blood in response to statins because their lipoprotein metabolism is similar to that of humans. Herein, lipid molecules were investigated by lipidome analysis in response to pitavastatin using WHHLMI rabbits. Various lipid molecules in the blood were measured using a supercritical fluid chromatography triple quadrupole mass spectrometry. Cholesterol and cholesterol ester blood concentrations decreased by reducing the secretion of very low density lipoproteins from the liver. Independent of the inhibition effects of cholesterol biosynthesis, the concentrations of some lipids with anti-inflammation and antioxidant effects (phospholipid molecules with n-6 fatty acid side chains, lysophosphatidylcholines, phosphatidylethanolamine plasmalogens, and ceramide molecules) were significantly altered. These findings may lead to further investigation of the mechanism of statin action.

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

Cited by 11 publications

References 39 publications

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

The Monocyte to High‐Density Lipoprotein Cholesterol Ratio in the Prediction for Atherosclerosis: A Retrospective Study in Adult Chinese Participants

Lipid Profiling of Serum and Lipoprotein Fractions in Response to Pitavastatin Using an Animal Model of Familial Hypercholesterolemia

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