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

63 Citations (Scopus)

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 2008

Fingerprint

Lipoprotein Lipase
Hypertriglyceridemia
Atherosclerosis
Diet
Chylomicrons
Hyperlipoproteinemia Type I
Foam Cells
Vascular Cell Adhesion Molecule-1
Chemokine CCL2
Human Umbilical Vein Endothelial Cells
Electron Spin Resonance Spectroscopy
Malondialdehyde
Coronary Disease
Epidemiologic Studies
Up-Regulation
Endothelial Cells
Observation

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet. / Zhang, Xiaohong; Qi, Rong; Xian, Xunde; Yang, Fei; Blackstein, Michael; Deng, Xuming; Fan, Jianglin; Ross, Colin; Karasinska, Joanna; Hayden, Michael R.; Liu, George.

In: Circulation Research, Vol. 102, No. 2, 02.2008, p. 250-256.

Research output: Contribution to journalArticle

Zhang, X, Qi, R, Xian, X, Yang, F, Blackstein, M, Deng, X, Fan, J, Ross, C, Karasinska, J, Hayden, MR & Liu, G 2008, 'Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet', Circulation Research, vol. 102, no. 2, pp. 250-256. https://doi.org/10.1161/CIRCRESAHA.107.156554
Zhang, Xiaohong ; Qi, Rong ; Xian, Xunde ; Yang, Fei ; Blackstein, Michael ; Deng, Xuming ; Fan, Jianglin ; Ross, Colin ; Karasinska, Joanna ; Hayden, Michael R. ; Liu, George. / Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet. In: Circulation Research. 2008 ; Vol. 102, No. 2. pp. 250-256.
@article{3811da13f1e547d5aa55b02d443c1082,
title = "Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet",
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.",
keywords = "Atherosclerosis, Hypertriglyceridemia, Lipoprotein lipase deficient mice, Lipoprotein oxidation",
author = "Xiaohong Zhang and Rong Qi and Xunde Xian and Fei Yang and Michael Blackstein and Xuming Deng and Jianglin Fan and Colin Ross and Joanna Karasinska and Hayden, {Michael R.} and George Liu",
year = "2008",
month = "2",
doi = "10.1161/CIRCRESAHA.107.156554",
language = "English (US)",
volume = "102",
pages = "250--256",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet

AU - Zhang, Xiaohong

AU - Qi, Rong

AU - Xian, Xunde

AU - Yang, Fei

AU - Blackstein, Michael

AU - Deng, Xuming

AU - Fan, Jianglin

AU - Ross, Colin

AU - Karasinska, Joanna

AU - Hayden, Michael R.

AU - Liu, George

PY - 2008/2

Y1 - 2008/2

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Hypertriglyceridemia

KW - Lipoprotein lipase deficient mice

KW - Lipoprotein oxidation

UR - http://www.scopus.com/inward/record.url?scp=41149172390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41149172390&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.107.156554

DO - 10.1161/CIRCRESAHA.107.156554

M3 - Article

C2 - 18032735

AN - SCOPUS:41149172390

VL - 102

SP - 250

EP - 256

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 2

ER -