Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet.
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.
Zhang
Xiaohong
X
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Beijing, China.
Qi
Rong
R
Xian
Xunde
X
Yang
Fei
F
Blackstein
Michael
M
Deng
Xuming
X
Fan
Jianglin
J
Ross
Colin
C
Karasinska
Joanna
J
Hayden
Michael R
MR
Liu
George
G
D000367:Age Factors; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D002914:Chylomicrons / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D015228:Hypertriglyceridemia / Q000150:complications*; D008071:Lipoprotein Lipase / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D014471:Umbilical Veins
D002914:Chylomicrons; D008071:Lipoprotein Lipase