Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet.
Open accessAbstract
Large-scale epidemiological studies have revealed a strong association between hypertriglyceridemia and coronary arteriosclerotic disease. However, there are conflicting reports whether the severe hypertriglyceridemia caused by lipoprotein lipase (LPL) deficiency is pro- or antiatherogenic. To determine the effect of LPL deficiency on atherosclerosis, we pursued long-term observation of the development of atherosclerotic lesions in an LPL gene deficient mouse model. At 4 months of age, homozygous LPL-deficient mice exhibited severe hypertriglyceridemia but no signs of aortic atherosclerotic lesions. At >15 months of age, these mice developed foam cell-rich atherosclerotic lesions at the aortic root, whereas wild-type and heterozygous mice were lesion-free at the same age. Further investigation revealed that plasma malondialdehyde levels in >15-month-old LPL-deficient mice were significantly higher than those of heterozygous and wild-type mice. Electron spin resonance analysis showed a marked increase in oxidative susceptibility of chylomicrons from the aged LPL-deficient mice. Incubation of chylomicrons from >15-month-old LPL-deficient mice with cultured human umbilical vein endothelial cells showed significantly increased upregulation of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, markers of enhanced endothelial activation, and enhanced adherence of human THP-1 mononuclear cells. These results clearly demonstrate the occurrence of spontaneous atherosclerosis in aged LPL-deficient mice mediated by the oxidation of chylomicrons and the activation of vascular endothelial cells.
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Severely hypertriglyceridemic animals, especially genetically modified mice, develop only early-stage lesions.
“Although there are a number of severely hypertriglyceridemic animals, especially genetically modified mice, these animals develop only early-stage lesions (138, 139).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [138]
The Discussion (page unavailable) reports that severely hypertriglyceridemic LPL-deficient mice developed fatty-streak lesions, supporting the claim for that model. It also describes other genetically modified hypertriglyceridemic mice but does not establish that their lesions were only early-stage, so the claim is broader than this source supports. (LLM, conf=0.86)
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Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline
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“Although there are a number of severely hypertriglyceridemic animals, especially genetically modified mice, these animals develop only early-stage lesions (138, 139).”
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- Authors
- Zhang, X., Qi, R., Xian, X., Yang, F., Blackstein, M., Deng, X., Fan, J., Ross, C., Karasinska, J., Hayden, M. R., & Liu, G.
- Affiliations
- University of British Columbia (CA)
- From the Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences (X.Z., R.Q., X.X., F.Y., G.L.), Ministry of Education; and Department of Pathology (M.B.), Peking University, Beijing, China; College of Animal Science and Veterinary Medicine (X.D.), Jilin University, Changchun, China; Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering (J.F.), University of Yamanashi, Japan; and Department of Medical Genetics (C.R., J.K...
- ORCID
- Venue
- Circulation Research
- Published
- 2008-02
- Volume
- 102
- Issue
- 2
- Pages
- 250-256
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2027572590
- Cited by
- 98
- References
- 37
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 11 · 2013: 9 · 2012: 6
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- National Key Research and Development Program of China
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- lipoprotein lipase deficiency, hypertriglyceridemia, spontaneous atherosclerosis, malondialdehyde, endothelial activation, VCAM-1, MCP-1, aging, endothelial cell adhesion
- MeSH terms
- Age Factors, Animals, Cells, Cultured, Chylomicrons, Endothelium, Vascular, Humans, Lipoprotein Lipase, Umbilical Veins, Hypertriglyceridemia, Mice, Knockout, Endothelial Cells, Atherosclerosis, Mice
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