Published online before print November 21, 2007, doi: 10.1161/CIRCRESAHA.107.156554
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Submitted on May 21, 2007
Revised on October 24, 2007
Accepted on November 8, 2007
Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet
Xiaohong Zhang ;
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.
* To whom correspondence should be addressed. 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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