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

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)250-256
Number of pages7
JournalCirculation research
Volume102
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Atherosclerosis
  • Hypertriglyceridemia
  • Lipoprotein lipase deficient mice
  • Lipoprotein oxidation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Zhang, X., Qi, R., Xian, X., Yang, F., Blackstein, M., Deng, X., Fan, J., Ross, C., Karasinska, J., Hayden, M. R., & Liu, G. (2008). Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet. Circulation research, 102(2), 250-256. https://doi.org/10.1161/CIRCRESAHA.107.156554