Published online before print November 21, 2007, doi: 10.1161/CIRCRESAHA.107.156554
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© 2008 American Heart Association, Inc.
Integrative Physiology |
Spontaneous Atherosclerosis in Aged Lipoprotein Lipase–Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet
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.
Correspondence to Dr George Liu, Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian District, 100083, Beijing, China. E-mail vangeorgeliu{at}gmail.com
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Abstract |
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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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Introduction |
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In recent human studies, hypertriglyceridemia (HTG) has been established as an independent risk factor for atherosclerosis by metaanalysis1 and confirmed in large-scale epidemiological studies.2 However, whether severe HTG with massive accumulation of chylomicrons (CMs) and/or very low density lipoprotein (VLDL) in plasma is pro- or nonatherogenic remains controversial.3
Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglycerides in CMs and VLDL in the plasma. This catalytic lipolysis initiates a cascade of lipoprotein particle conversion, including the formation of low density lipoprotein (LDL) and other remnant lipoproteins, and also initiates the remodeling of high density lipoprotein (HDL). LPL deficiency in human patients results in severe HTG with accumulation of CMs, and low levels of LDL and HDL.4 This type of lipoprotein profile is generally thought to be nonatherogenic because CMs are too large to penetrate into sub-endothelial space of arterial walls.5 The low HDL level in these patients would be considered as pro-atherogenic, but may not be a crucial factor because its influence may be counteracted by coexistence of extremely low LDL levels which result in markedly reduced atherogenic potential.6 Therefore, it was generally accepted that the incidence of coronary artery disease (CAD) in LPL deficient patients with severe HTG was low, until Benlian et al reported that all of 4 LPL deficient patients developed angiographically defined atherosclerotic lesions.7 Subsequent case reports have shown that subjects with LPL deficiency and severe HTG were either associated with significant systemic atherosclerotic lesions or had none at all.8–10
This discrepancy in the susceptibility of LPL-deficient severe HTG individuals to atherosclerosis was partially explained by the presence or absence of noncatalytic LPL protein. Noncatalytic LPL can act as a molecular bridge between proteoglycans and different lipoprotein receptors to facilitate lipoprotein uptake by cells such as macrophages.11 Therefore, macrophage secretion of LPL, even though catalytically inactive, might enhance foam cell formation through increased uptake of atherogenic lipoproteins. However, in these case reports noted above, it was impossible to control for genetic heterogenicity, dietary habit and lifestyle, all of which might significantly affect the development of atherosclerosis.
Several animal models of severe HTG have been generated. These include genetically manipulated mice and mammals other than rodents. Two mouse models, human apolipoprotein (apo)CI and apoCIII transgenic mice on apoE–null background, exhibit severe HTG with nearly two-fold increased levels of cholesterol (Ch) than apoE-deficient mice.12,13 However, significantly more atherosclerotic lesions were found in apoCI transgenic apoE–null mice, as compared with apoE–null mice, whereas apoCIII transgenic apoE–null mice only showed lesions similar to apoE–null mice. Ob/Ob mice with a mutation in the leptin gene crossed with LDL receptor–null mice also presented unexpected severe HTG and hypercholesterolemia with more atherosclerotic lesions than either of the mutant mouse strains alone.14 Whereas alloxan-induced diabetic rabbits fed high-Ch diet developed severe HTG, the atherosclerotic lesions in these rabbits were significantly reduced in the course of 3 months of observation, compared with the nondiabetic rabbits fed high-Ch diet.15 Atherogenesis has not been studied in LPL gene mutated cats and minks, both of which have severe HTG.16,17 Unlike human LPL deficiency, which is characterized by a marked reduction in plasma LDL and HDL, animal models of severe HTG have less dramatic changes in LDL and HDL.
We used a mouse model of LPL deficiency18 to investigate the association between atherogenesis and severe HTG. LPL deficiency in mice is normally lethal in neonates. We have rescued homozygous LPL-deficient mice through adenovirus-mediated gene transfer at birth.18,19 In addition to massive accumulation of CMs in plasma, these mice display strikingly reduced plasma HDL and LDL. Moreover, these mice have a normal life span, which allowed us to follow the natural development of atherosclerosis without additional environmental manipulations and particularly without the use of a high fat atherogenic diet.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org. LPL-deficient mice were rescued by intramuscular administration of an adenoviral vector coding a human LPL mutant. In all experiments, both male and female mice in different age groups were used in approximately equal ratios. Sections of aortic root were stained with oil red O and quantified and were also stained for macrophages, vascular cell adhesion molecule (VCAM)-1, and
-actin with corresponding antibodies. Ch was stained with filipin. CM was isolated for determination of oxidation by electron spin resonance and for evaluation of adhesion of macrophages to endothelial cells. Expression of MCP-1 and VCAM-1 in endothelial cells was detected by real-time RT-PCR. Plasma lipids, malondialdehyde (MDA), and LPL activity were assayed by conventional methods. The results are expressed as means±SD. Statistical significance was determined by analysis of the variance (ANOVA), and probability values <0.05 were regarded as significant. |
Results |
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Loss of LPL Activity Causes Significant Dyslipidemia in LPL-Deficient Mice
LPL activity in PHP of adult LPL deficient animals was almost undetectable (<7% of normal) (Table). LPL heterozygous mice showed a trend toward reduced LPL activity compared with wild-type mice. Plasma TGs and TC levels in LPL deficient (LPL–/–) mice were significantly higher than LPL heterozygous and wild-type mice (Table).There was no significant difference in TG and TC levels between LPL heterozygous and wild-type mice, although TG levels of LPL heterozygous mice were slightly higher than those of wild-type mice. HDL-Ch levels were markedly decreased in LPL-deficient mice to only 1±2 mg/dL (0% to 2% of normal levels).
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Evidence of Atherosclerotic Lesions in the Aortic Sinuses of Aged LPL-Deficient Mice
Atherosclerotic lesions were found in the aortic sinuses of >15-month-old LPL-deficient mice regardless of sex (Figure 1A). LPL-deficient mice had fatty streaks that consisted of foam cells. Quantitative analysis of atherosclerosis was performed by measuring the extent of oil red O staining of cryosections from the aortic sinuses. The mean lesion area (µm2±SD) was 4.43±2.74x104 (Figure 1B). In contrast, both LPL heterozygous and wild-type mice of similar age had no detectable lesions in the aortic sinuses. The oil red O–positive en face lesions were found in the aortic arches and thoracic aortas in aged LPL-deficient mice, especially in the brachiocephalic trunk arteries (Figure 1C). In addition, the intima of aged LPL-deficient mice was markedly thicker than heterozygous and wild-type mice of the same age. Immunohistochemical staining of the aged LPL-deficient mice with macrophage-specific antibodies identified foam cells derived from macrophages as the major cell type present in the aortic root lesions (Figure 2, third column). Mac-3–positive area was 33.5±5.9% more than total lesion area by morphometric quantification. Filipin staining indicated that the lipid components were mainly composed of Ch (Figure 2, second column), even though the plasma TG levels were extremely high in LPL-deficient mice. VCAM-1, the marker for endothelial activation, was also expressed strongly on the endothelium of the aged LPL-deficient mice (Figure 2, fourth column), whereas in wild-type and heterozygous mice, neither Mac-3 nor VCAM staining was discernable in aortic sinus. However, the aortic lesions in LPL-deficient mice did not contain much smooth muscle cells as stained by anti–-actin antibody (Figure 2, fifth column), indicating the lesions were not in advanced stage. In the LPL-deficient mice, mild to moderate lipid deposition was found in the liver, kidney, and spleen at 4 months of age (data not shown).
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Increased Plasma MDA Levels in LPL-Deficient Mice
Because of massive accumulation of TG-rich CMs in plasma, which may result in oxidative modification of lipid moieties in CMs, we measured plasma MDA levels. It was found that plasma MDA levels in LPL-deficient mice were significantly higher than those of heterozygous and wild-type mice in both young and aged animals (P<0.01, Figure 3). This indicated that oxidative damage in LPL-deficient mice was more severe compared with heterozygous and wild-type mice. Though plasma MDA levels of heterozygous and wild-type mice did not change significantly with age there was significant increase in MDA levels between young and aged LPL-deficient mice (12.8±1.2 versus 21.3±4.2 mmol/mL; P<0.01).
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Elevated Oxidative Susceptibility of CMs in Aged LPL-Deficient Mice
The recordings of electron spin resonance spectra showed dramatically different patterns of CMs from young and aged LPL-deficient mice (Figure 4A). Quantitation of height of the first peak in electron spin resonance recordings demonstrated clearly that the electron spin resonance signal intensity of the 5-dimethyl-1-pyrroline N-oxide (DMPO-OH) adduct from CMs of aged LPL-deficient mice was increased 
8 times when compared with that from CMs of young mice, which indicated that CMs from aged LPL-deficient mice were more susceptible to oxidation than those from younger mice (Figure 4B).
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Enhanced Monocyte Adhesion to HUVECs and Upregulation of Adhesion Molecule Expression in HUVECs by CMs From Aged Mice
Expression of adhesion molecules is a hallmark of endothelial cell activation and of early atherosclerosis. To investigate whether CMs from aged mice, which underwent extensive oxidation, promote mononuclear cell adhesion to endothelial cells, in vitro cultured human umbilical vein endothelial cell (HUVECs) were incubated with CMs from aged and young LPL-deficient mice to mimic in vivo environment. Stimulation with CMs (TG=150 mg/dL) from aged mice produced an 2.2-fold increase in adhesion of THP-1 cells to HUVEC monolayers compared with the CMs from young mice (Figure 5). Rat mesenteric CMs diluted to TG levels at 150 mg/dL as negative control had similar effect as CMs from young mice (Figure I in the online data supplement). As other controls, human native LDL (Ch=20 mg/dL) did not alter adhesion of THP1 to HUVEC cells, whereas oxidized LDL and lipoprotein remnant from apoE–/– mice at similar concentration of Ch greatly enhanced the macrophage adhesion to HUVEC (supplemental Figure I). At the same time, we examined the effect of CMs on expression of VCAM-1 and MCP-1 in HUVECs. Treatment of HUVECs with CMs from aged mice resulted in a significant increase in the cell-surface expression of VCAM-1 and MCP-1, compared with CMs from young mice (Figure 6). These findings collectively demonstrated that CMs from aged mice potently promoted production of chemotactic cytokines and adhesion of mononuclear cells to HUVECs, suggesting that these CMs might increase vascular inflammation.
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Discussion |
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In the present study, we show that LPL-deficient mice with severe HTG develop distinct atherosclerotic lesions of fatty streak, composed of mainly Ch, at the aortic root at >15 months of age on a regular chow diet, whereas wild-type and heterozygous LPL-deficient mice without severe HTG at the same age were virtually lesion-free over the entire aorta.
Mice are well known as species resistant to atherosclerosis, although susceptible strains, such as C57B6, will form aortic lesions when fed a custom-designed high-Ch diet, as described by Paigen et al.20 On the other hand, there are genetically modified mouse models with hypercholesterolemia, which develop spontaneous atherosclerosis. For example, atherosclerotic lesions occurred as early as 3 months of age in apoE-deficient mice on a normal rodent chow diet.21 LDL receptor gene inactivated mice also spontaneously develop minute but discernable aortic lesions at age of 6 months.22 Over such genetic backgrounds, the role of numerous genes in atherogenesis have been assessed by transgenic addition or knockout subtraction.23 It is worth noting that transgenic expression of apo(a) alone also resulted in significant aortic lesions in mice maintained on a low-fat diet for 66 weeks,24 providing direct evidence for a causal relationship between apo(a) and atherosclerosis.
In an earlier study, we reported that the majority of plasma lipoproteins in LPL-deficient severe HTG mice were TG-rich large lipoproteins, namely CM- and VLDL-like particles, whereas HDL remained markedly reduced in these mice.25 Although reduced HDL has long been recognized as a major risk factor for CAD in humans, extremely low HDL-Ch was not associated with increased susceptibility to atherosclerosis in mice.26 Therefore, in seeking a mechanism responsible for such spontaneous atherosclerosis in aged severe HTG mice, we hypothesized that although the massive accumulation of large TG-rich lipoproteins could not cross through the arterial wall and be retained in the subendothelial space, they may instead directly damage arterial endothelial cells, which would result in initiation of atherogenesis. In support of this hypothesis, these experiments have shown that CMs from the aged HTG mice had a stronger effect on upregulation of MCP-1 and VCAM-1 expression in cultured endothelial cells than CMs from younger mice. MCP-1 and VCAM-1 are generally regarded as sensitive markers for endothelial activation and early atherogenesis because of their role in recruitment of macrophages to arterial walls.27 Furthermore, in a functional assay for macrophage adhesion, more macrophages were adhered to cultured endothelial cells in the presence of CMs from aged mice, compared with those from younger mice. After finding that oxidation indicator MDA levels were significantly increased in aged mice, electron paramagnetic resonance analysis further revealed strikingly 8-fold increase in oxidative susceptibility in CMs from aged mice, compared with those from young mice.
Our findings contradict 2 previous studies in diabetic Ch-fed rabbits28 and apoC-III transgenic mice on apoE-deficient background,12 which demonstrated that the large lipoprotein particles present in severe HTG were nonatherogenic. In fact, a similar conclusion could also be made from this study, if hypercholesterolemic apoE-deficient mice were chosen for comparison. Because well documented, apoE-deficient mice exhibited high levels of Ch similar to LPL-deficient severe HTG mice, but these mice showed much lower plasma TG levels and pronounced atherosclerotic lesions. The lesion size in LPL-deficient severe HTG mice at age >15 months, however, was even smaller than that of apoE-deficient mice at age of 3 months (performed in our laboratory in other experiments). These results suggest that large TG-rich particles such as CMs and VLDL may be less atherogenic than those of small Ch-rich particles (remnant lipoproteins) in mice.
The findings of the present study also need to be reconciled with the well-accepted understanding that arterial wall LPL plays a proatherogenic role. In fact, other work done recently by our laboratory did document a proatherogenic effect by overexpression of either active or inactive LPL in both endothelial intact and damaged carotid arteries in rabbits and in mice.29,30 A likely explanation is that although lack of LPL at the arterial wall per se is associated with low potential of atherogenesis this lack of LPL may not provide complete protection against atherosclerosis when oxidized atherogenic lipoproteins are present in the plasma at high levels. Even though CMs are well documented to be nonatherogenic lipoproteins, they may be modified oxidatively, as documented in this study, and show atherogenic potential through activation of endothelial cells to a certain extent, when present at high concentrations over a long period of time. Further verification of this hypothesis could be made by assessment of lesion formation in LPL-deficient mice crossed with either apoE or LDL-R deficient mice. With such double mutant mice, we believe that it is unlikely that lack of LPL at arterial wall will be found to provide complete protection against atherosclerosis.
Therefore, considering the spontaneous nature of atherogenesis in aged LPL-deficient HTG mice it can be concluded that the large TG-rich lipoprotein particles are atherogenic, although they are not as potent as the Ch-rich lipoprotein particles in apoE-deficient mice. However, it should be also noted that these large TG-rich particles in aged LPL-deficient mice may not be identical to CMs in humans because over a long period of time, these particles are modified in certain ways, becoming remnant-like particles and atherogenic. Hence, whether TG-rich particles, which are similar to native human CMs or VLDL, are atherogenic is still unanswered.
To further expand our understandings of the atherogenic nature of large TG-rich lipoprotein in the humans, appropriate comparison among severe HTG, severe hypercholesterolemia, and normal subjects should be performed with more sensitive methodologies to detect minute changes in the atherosclerotic lesions. Following such comparison, a careful evaluation of the risk of severe HTG in atherogenesis could then be made, so as to develop proper clinical direction for better control of the disorder.
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Acknowledgments |
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Sources of Funding
This work was supported in part by the Major National Basic Research Program of the People’s Republic of China (G2006CD503801), the National Natural Science Foundation of the People’s Republic of China (grant 30470695), the Program for Changjiang Scholars Innovative Research Team in University (to G.L.); and the Sino-Canada Joint Health Research Initiative (to M.R.H. and G.L.). M.R.H. holds a Canada Research Chair in Molecular Medicine. J.K. is a Heart and Stroke Foundation of Canada postdoctoral fellow.
Disclosures
None.
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Footnotes |
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*The first two authors contributed equally to this work.
Original received May 21, 2007; revision received October 24, 2007; accepted November 8, 2007.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation. 2002; 105: 310–315.
2. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease. 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation. 2007; 115: 450–458.
3. Goldberg IJ: Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res. 1996; 37: 693–707.[Abstract]
4. Santamarina-Fojo S. The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am. 1998; 27: 551–567.[CrossRef][Medline] [Order article via Infotrieve]
5. Brunzell JD. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. Vol 2. McGraw-Hill: New York; 1995: 1913–1932.
6. Clee SM, Bissada N, Miao F, Miao L, Marais AD, Henderson HE, Steures P, McManus J, McManus B, LeBoeuf RC, Kastelein JJ, Hayden MR. Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis. J Lipid Res. 2000; 41: 521–531.
7. Benlian P, De Gennes JL, Foubert L, Zhang H, Gagne SE, Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. N Engl J Med. 1996; 335: 848–854.
8. Saika Y, Sakai N, Takahashi M, Maruyama T, Kihara S, Ouchi N, Ishigami M, Hiraoka H, Nakamura T, Yamashita S Matsuzawa Y. Novel LPL mutation (L303F) found in a patient associated with coronary artery disease and severe systemic atherosclerosis. Eur J Clin Invest. 2003; 33: 216–222.[CrossRef][Medline] [Order article via Infotrieve]
9. Ebara T, Okubo M, Horinishi A, Adachi M, Murase T, Hirano T. No evidence of accelerated atherosclerosis in a 66-yr-old Chylomicronemia patient homozygous for the nonsense mutation (Tyr61-Stop) in the lipoprotein lipase gene. Atherosclerosis. 2001; 159: 375–379.[CrossRef][Medline] [Order article via Infotrieve]
10. Kawashiri M, Higashikata T, Mizuno M, Takata M, Katsuda S, Miwa K, Nozue T, Nohara A, Inazu A, Kobayashi J, Koizumi J, Mabuchi H. Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis. J Clin Endocrinol Metab. 2005; 90: 6541–6544.
11. Beisiegel U, Weber W, Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 1991; 88: 8342–8346.
12. Conde-Knape K, Bensadoun A, Sobel JH, Cohn JS, Shachter NS. Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase. J Lipid Res. 2002; 43: 2136–2145.
13. Ebara T, Ramakrishnan R, Steiner G, Shachter NS. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein. Eur J Clin Invest. 1997; 99: 2672–2681.[CrossRef]
14. Hasty AH, Shimano H, Osuga H, Namatame I, Takahashi A, Yahagi N, Perrey S, Iizuka Y, Tamura Y, Amemiya-Kudo M, Yoshikawa T, Okazaki H, Ohashi K, Harada K, Matsuzaka T, Sone K, Gotoda T, Nagai R, Ishibashi S, Yamada N. Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor. J Bio Chem. 2001; 276: 37402–37408.
15. Nordestgaard BG, Zilvetsmit DB. Large lipoproteins are excluded from the arterial wall in diabetic Ch-fed rabbits. J Lipid Res. 1988; 29: 1491–1500.[Abstract]
16. Ginzinger DG, Lewis ME, Ma Y, Jones BR, Liu G, Jones SD. Hayden MR. A mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia in a colony of domestic cats. J Clin Invest. 1996; 97: 1257–1266.[Medline] [Order article via Infotrieve]
17. Christophersen B, Nordstoga K, Shen Y, Olivecrona T, Olivecrona G. Lipoprotein lipase deficiency with pancreatitis in mink: biochemical characterization and pathology. J Lipid Res. 1997; 38: 837–846.[Abstract]
18. Ross CJ, Liu G, Kuivenhoven JA, Twisk J, Rip J, van Dop W, Excoffon KJ, Lewis SM, Kastelein JJ, Hayden MR. Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation. Arterioscler Thromb Vasc Biol. 2005; 25: 2143–2150.
19. Strauss JG, Frank S, Kratky D, Hammerle G, Hrzenjak A, Knipping G, von Eckardstein A, Kostner GM, Zechner R. Adenovirus-mediated rescue of lipoprotein lipase-deficient mice. Lipolysis of triglyceride-rich lipoproteins is essential for high density lipoprotein maturation in mice. J Biol Chem. 2001; 276: 36083–36090.
20. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987; 68: 231–240.[CrossRef][Medline] [Order article via Infotrieve]
21. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.[CrossRef][Medline] [Order article via Infotrieve]
22. Sanan DA, Newland DL, Tao R, Marcovina S, Wang J, Mooser V, Hammer RE, Hobbs HH. Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). Pro Natl Acad Sci U S A. 1998; 95: 4544–4549.
23. Ohashi R, Mu H, Yao Q, Chen C. Cellular and molecular mechanisms of atherosclerosis with mouse models. Trends Cardiovasc Med. 2004; 14: 187–190.[CrossRef][Medline] [Order article via Infotrieve]
24. Berg K, Svindland A, Smith AJ, Lawn RM, Djurovic S, Alestrom A, Alestrom P, Eliassen K. Spontaneous atherosclerosis in the proximal aorta of LPA transgenic mice on a normal diet. Atherosclerosis. 2002; 163: 99–104.[CrossRef][Medline] [Order article via Infotrieve]
25. Ross CJ, Twisk J, Meulenberg JM, Liu G, van den Oever K, Moraal E, Hermens WT, Rip J, Kastelein JJ, Kuivenhoven JA, Hayden MR. Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. Hum Gene Ther. 2004; 15: 906–919.[Medline] [Order article via Infotrieve]
26. Li H, Reddick RL, Maeda N. Lack of apoA-I is not associated with increased susceptibility to atherosclerosis in mice. Arterioscler Thromb. 1993; 13: 1814–1821.
27. Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004; 95: 858–866.
28. Minnich A, Zilversmit DB. Impaired triacylglycerol catabolism in hypertriglyceridemia of the diabetic, Ch-fed rabbit: a possible mechanism for protection from atherosclerosis diabetic Ch-fed rabbits. Biochim Biophys Acta. 1989; 1002: 324–332.[Medline] [Order article via Infotrieve]
29. Wu X, Wang J, Fan J, Chen M, Chen L, Huang W, Liu G. Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall. Atherosclerosis. 2006; 187: 65–73.[CrossRef][Medline] [Order article via Infotrieve]
30. Wang J, Xian X, Huang W, Chen L, Wu L, Zhu Y, Fan J, Ross C, Hayden MR, Liu G. Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and apoE-deficient mice. Arterioscler Thromb Vasc Biol. 2007; 27: 197–203.
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