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(Circulation Research. 2008;102:250.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet

Xiaohong Zhang^*, Rong Qi^*, Xunde Xian, Fei Yang, Michael Blackstein, Xuming Deng, Jianglin Fan, Colin Ross, Joanna Karasinska, Michael R. Hayden, George Liu

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., M.R.H.), University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.

Correspondence to Dr George Liu, Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian District, 100083, Beijing, China. E-mail vangeorgeliu{at}gmail.com

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.

Key Words: atherosclerosis • hypertriglyceridemia • lipoprotein lipase deficient mice • lipoprotein oxidation

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