Copyright © 2004, European Society of Cardiology
Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase
aCardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
bInstitute for Experimental Animals, Kobe University School of Medicine, Kobe 650-0017, Japan
cDepartment of Pharmacology, Dalian Medical University, Dalian 116027, PR China
dSaga University, Saga 849-8501, Japan
eInstitute of Cardiovascular Sciences, Peking University, Beijing 100083, PR China
* Corresponding author. Tel.: +81 298 53 3262; fax: +81 298 53 3262. Email address: J-LFAN{at}md.tsukuba.ac.jp
Objective: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency.
Methods: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits.
Results: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006–1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04–1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits.
Conclusions: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.
KEYWORDS Lipoprotein lipase; WHHL rabbits; Transgenic rabbits; Hypercholesterolemia; Hypertriglyceridemia; Atherosclerosis
1 These authors contributed equally to this work.
Time for primary review 22 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Qiu and J. S. Hill Endothelial lipase enhances low density lipoprotein binding and cell association in THP-1 macrophages Cardiovasc Res, December 1, 2007; 76(3): 528 - 538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Qiu, A. C. Ho, W. Yu, and J. S. Hill Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion J. Lipid Res., February 1, 2007; 48(2): 385 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liang, E. Liu, Y. Yu, S. Kitajima, T. Koike, Y. Jin, M. Morimoto, K. Hatakeyama, Y. Asada, T. Watanabe, et al. Macrophage Metalloelastase Accelerates the Progression of Atherosclerosis in Transgenic Rabbits Circulation, April 25, 2006; 113(16): 1993 - 2001. [Abstract] [Full Text] [PDF]
|
|