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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1831.)
© 2000 American Heart Association, Inc.

Thrombosis

Hyperlipidemia Promotes Thrombosis After Injury to Atherosclerotic Vessels in Apolipoprotein E–Deficient Mice

Daniel T. Eitzman; Randal J. Westrick; Zuojun Xu; Julia Tyson; David Ginsburg

From the Cardiovascular Research Center (D.T.E., Z.X.) and Division of Molecular Medicine and Human Genetics (D.G.), Department of Internal Medicine, and the Howard Hughes Medical Institute (R.J.W., J.T., D.G.), University of Michigan Medical Center, Ann Arbor.

	Abstract

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Abstract—The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels. The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an atherosclerotic plaque. Fifteen apolipoprotein E–deficient mice were maintained on normal chow until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common carotid artery immediately proximal to the carotid bifurcation, where an atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive thrombi, determined by cessation of blood flow, 44±5 minutes (mean±SEM) after photochemical injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27±3 minutes (P<0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus formation at sites of atherosclerosis after vascular injury.

Key Words: carotid artery • transgenic mice • cholesterol • plaque • rose bengal

	Introduction

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Arterial thrombosis after plaque disruption is the critical event leading to acute vascular syndromes, including myocardial infarction, unstable angina pectoris, and stroke.¹ Elevated cholesterol levels increase the risk of arterial thrombotic events in patients with atherosclerosis, and cholesterol-lowering therapy reduces the risk of myocardial infarction and stroke to an extent that is out of proportion to the reduction in plaque size.² Alterations in lipid levels have been proposed to influence thrombosis by modifying the activity of coagulation proteins,^{3 4} platelets,⁵ and fibrinolytic factors.^{6 7} However, the effect of acute high fat feeding–induced hypercholesterolemia on the development of occlusive thrombosis after injury to an atherosclerotic artery has not been extensively analyzed.

We have developed a model of atherosclerotic plaque disruption with the use of atherosclerosis-prone mice that leads to occlusive arterial thrombosis. This model was used to analyze the effect of high fat feeding on the time to occlusive thrombosis.

	Methods

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Mice
ApoE-deficient (apoE^-/-) mice were purchased from Jackson Labs, Bar Harbor, Me. These mice were backcrossed to C57BL/6J mice for at least 10 generations. All mice were maintained on normal chow (PicoLab Rodent Chow) for 30 weeks and then either switched to a high fat chow (Teklad Adjusted Calories Western-Type Diet, 21% [wt/wt] fat [polyunsaturated/saturated 0.07], 0.15% [wt/wt] cholesterol, 19.5% [wt/wt] casein, and no sodium cholate) or maintained on normal chow 5 days before vascular injury. Mice were genotyped by using 3 primer sets that specifically amplified the wild-type or knockout apoE allele (5'-CCTAGCCGAGGGAGAGCCG-3', 5'-TGTGACTTGGGAGCTCTGCAGC-3', and 5'-GCCGCCCCGA- CTGCATCT-3'). An additional group of 6-week-old apoE^-/- mice was similarly maintained on normal chow or fed high fat chow for 5 days before vascular injury. All animal care and experimental procedures complied with the Principles of Laboratory and Animal Care established by the National Society for Medical Research and were approved by the University of Michigan Committee on Use and Care of Animals.

Induction of Carotid Arterial Thrombosis at Site of Atherosclerosis
Male apoE^-/- mice (aged 6 and 30 weeks) were anesthetized with 1.5 mg intraperitoneal sodium pentobarbital (Butler). Mice were then secured in the supine position and placed under a dissecting microscope (Nikon SMZ-2T, Mager Scientific, Inc). After a midline cervical incision, the right common carotid artery was isolated, and a Doppler flow probe (model 0.5 VB, Transonic Systems) was applied. The probe was connected to a flowmeter (Transonic model T106) and interpreted with a computerized data acquisition program (Windaq, DATAQ Instruments). Rose bengal (Fisher Scientific) was diluted to 10 mg/mL in PBS and then injected into the tail vein in a volume of 0.12 mL at a concentration of 50 mg/kg by use of a 27-gauge Precision Glide needle with a 1-mL latex-free syringe (Becton Dickinson and Co). Just before injection, a 1.5-mW green light laser (540 nm, Melles Griot) was applied immediately proximal to the carotid bifurcation from a distance of 6 cm for 60 minutes or until occlusive thrombosis occurred. Flow in the vessel was monitored continuously from the onset of injury.⁸

Plasma Lipid Assays
Blood from mice fasted overnight was collected by retro-orbital bleeding into heparin-coated capillary tubes. Plasma was retrieved after centrifugation for 10 minutes at 5000g. Plasma lipid levels were assayed within 4 hours of collection by use of a Vitros analyzer (Ortho Diagnostics, Inc). Samples for total cholesterol determination were diluted 5-fold, and triglycerides levels were measured from undiluted plasma.

Platelet Aggregation
Whole blood was obtained from the inferior vena cava of mice anesthetized with pentobarbital. Platelet-rich plasma was obtained as previously described.⁹ Samples were simultaneously isolated and analyzed in pairs, 1 from each group. Platelet reactivity was assessed in response to ADP by use of a Platelet Aggregation Profiler (BIODATA Corp) according to the manufacturer’s instructions. Aggregation baselines (100% and 0%) were set with corresponding platelet-poor and platelet-rich plasmas.

Histology
To confirm plaque-associated thrombus, carotid arterial segments subjected to injury were excised and embedded in paraffin. Sections were then stained with hematoxylin and eosin.

Statistical Analysis
The significance of differences between groups was determined by the Student t test. A value of P<0.05 was considered significant.

	Results

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Murine Model of Plaque Disruption
ApoE^-/- mice develop atherosclerotic lesions throughout the vasculature with a predilection for bifurcation sites.¹⁰ By 30 weeks of age, extensive atherosclerosis is present. The carotid bifurcation was selected because a consistent atherosclerotic lesion forms at this site (Figure 1A) and because the common carotid artery is conducive to monitoring with a flow probe.⁸ Control experiments in 30-week-old apoE^-/- mice revealed that rose bengal at a dose of 50 mg/kg with the laser light source 6 cm away from the carotid artery injury site produced occlusive thrombosis, which was confirmed with hematoxylin and eosin staining of tissue sections. Twenty-four hours after injury and after the occlusive thrombus had been partially lysed, residual thrombus adherent to sites of atherosclerotic plaque was apparent (Figure 1B).

View larger version (146K): [in this window] [in a new window]   Figure 1. Photochemically induced atherothrombosis. The carotid arteries of 30-week-old apoE-deficient mice underwent photochemical injury to an atherosclerotic plaque immediately proximal to the carotid bifurcation. A, Uninjured atherosclerotic lesion. P indicates plaque. B, Injured atherosclerotic segment 24 hours after photochemical injury to demonstrate persistent thrombus (T) associated with the atherosclerotic lesion.

Effect of High Fat Feeding on Plasma Lipids and Time to Occlusive Thrombus Formation
To determine whether the development of carotid artery occlusion at sites of atherosclerosis was affected by acute changes in diet, the mice were either maintained on normal chow or fed high fat chow for 5 days before carotid injury. This dietary manipulation increased total cholesterol levels from 587±24 mg/dL (mean±SEM, n=5) to 921±77 mg/dL (n=5, P<0.005), with no significant change in triglyceride levels (Figure 2A). Nine apoE^-/- mice that were maintained on normal chow formed occlusive thrombus at the site of light application a mean of 44±5 minutes after initiation of injury, and 6 apoE^-/- mice fed high fat chow developed occlusive thrombosis a mean of 27±3 minutes after injury (Figure 2B, P<0.02). All 30-week-old animals presented grossly evident lesions involving the carotid bifurcation, which were confirmed by histology and appeared to be of similar size. Histological analysis immediately after injury revealed occlusive thrombi that appeared similar between the groups. To determine whether the effect of high fat feeding on the time to occlusive thrombosis was dependent on the presence of an atherosclerotic plaque, 6-week-old apoE^-/- mice that lack overt atherosclerosis¹⁰ were subjected to the same dietary manipulation and photochemical injury. The time to occlusion was 78±8 minutes in mice fed normal chow (n=6) and 63±4 minutes in mice fed high fat chow (n=6) for 5 days before injury (P=0.13).

View larger version (25K): [in this window] [in a new window]   Figure 2. Effect of high fat feeding on plasma lipids and time to occlusive thrombosis. A, Cholesterol levels were significantly increased (*P<0.005) in mice fed high fat chow for 5 days (open bar) compared with mice fed normal chow (hatched bar). Triglyceride levels were unchanged. B, In atherosclerotic 30-week-old apoE-/- mice, 5 days of high fat feeding was associated with significant shortening of the time to occlusive thrombosis (*P<0.02).

Effect of High Fat Feeding on Platelet Aggregation
To determine whether the shortened time to occlusion after high fat feeding was associated with enhanced platelet reactivity, platelet aggregation studies were performed on 30-week-old apoE^-/- mice with and without the high fat dietary manipulation. Platelet counts were similar between the 2 groups, with a mean count of 1.4x10⁹ platelets per milliliter in the high fat chow group and 1.7x10⁹ platelets per milliliter in the normal chow group. Platelet counts were adjusted to 2.5x10⁸ per milliliter by the addition of citrated platelet-poor plasma. Mean maximal platelet aggregation in response to 10 µmol/L ADP was increased in mice after the brief period of high fat feeding (44±11%, n=5) compared with mice on normal chow (24±10%, n=5; P<0.003).

	Discussion

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Hypercholesterolemia is a well-established risk factor for the development and complications of atherosclerosis.^{11 12} Several recent trials have demonstrated the beneficial effect of potent lipid-lowering therapies on the incidence of myocardial infarction.^{13 14 15 16} This salutary effect is observed soon after the onset of treatment and despite the minimal effects of lipid lowering on the size of the atherosclerotic lesion.^{2 17} Thus, acute changes in lipids appear to have significant effects on factors influencing acute thrombosis in the setting of atherosclerosis.

Atherosclerosis-prone mice are a useful model for assessing the role of various determinants of thrombosis at the site of an atherosclerotic lesion. ApoE^-/- mice develop hyperlipidemia and extensive atherosclerosis, both of which are enhanced by high fat feeding. Previous studies have demonstrated that high fat chow produces a marked elevation in plasma cholesterol levels in apoE^-/- mice, from a baseline of 600 mg/dL for mice on regular chow to a peak of 2700 mg/dL, which plateaus at 2 weeks after the initiation of high fat feeding.¹⁸ Therefore, by dietary manipulation, the effect of high fat chow can be studied. Photochemical injury is a relatively noninvasive method of inducing endothelial injury and thrombosis that is particularly useful for small animals such as mice.^{8 19 20} In addition, the endothelial injury elicited by rose bengal is mediated by a superoxide anion,²¹ a type of injury that may occur endogenously in the progression of atherosclerosis²² and contribute to plaque disruption.

Our data indicate that hyperlipidemia induced by high fat feeding in apoE^-/- mice promotes occlusive thrombus formation after vascular injury. The brief period of high fat feeding in these experiments produced a relatively modest elevation of cholesterol, approximately one third the level attained with more prolonged feeding. This milder elevation may be more relevant to humans with hyperlipidemia. These studies indicate that acute changes in cholesterol are especially relevant in the setting of an atherosclerotic plaque. Although a trend toward shorter occlusion times with high fat feeding was noted in young apoE^-/- mice before the development of overt atherosclerosis, this did not achieve statistical significance. The occlusion times of young apoE^-/- mice were actually slightly longer than occlusion times previously reported for wild-type C57BL/6J mice,⁸ even though the mean cholesterol level is 94 mg/dL in wild-type C57BL/6J mice compared with 587 mg/dL in apoE^-/- mice maintained on regular chow.¹⁸ Although we cannot exclude an additional antiplatelet effect of apoE deficiency, this supports the hypothesis that thrombi forming at the site of a preexisting atherosclerotic plaque are more susceptible to the effects of acute lipid alterations than thrombi forming in normal arteries. However, it is also possible that a more prolonged period of high fat feeding would produce a greater effect on nonatherosclerotic vessels.

The mechanism of these acute changes in plasma cholesterol on the development of thrombosis is unclear. It may be that the enhanced platelet aggregation observed in these studies after high fat feeding is especially relevant in the thrombotic milieu of an atherosclerotic plaque. The enhanced thrombogenicity of the plaque is apparent by the shortened occlusion times in 30-week-old versus 6-week-old mice, regardless of diet. Additional mechanisms may also be playing important roles. For example, monocyte-derived macrophages, which accumulate in atherosclerotic plaques, express tissue factor that is positively regulated by oxidized LDL and cholesterol.²³ In addition, LDL, which increases in apoE^-/- mice after high fat feeding,¹⁸ has been shown to bind and inhibit the anticoagulant function of an important regulator of tissue factor, tissue factor pathway inhibitor.²⁴ Thus, acute changes in LDL could lead to enhanced tissue factor expression, which would be particularly relevant at the site of an atherosclerotic plaque.

Although there are important differences in the hyperlipidemia observed in this mouse model compared with common human hyperlipidemia, this model may be useful in further elucidating the factors involved in atherothrombosis.

	Acknowledgments

 
This grant was supported by National Institutes of Health grants HL-036195-02 (D.T.E.) and HL-57345 (D.G.). D. Ginsburg is a Howard Hughes Medical Institute Investigator.

	Footnotes

 
Reprint requests to Daniel T. Eitzman, MD, University of Michigan Medical Center, MSRB III, Room 7301, 1150 Medical Center Dr, Ann Arbor, MI 48109-0644.

Received February 28, 2000; accepted April 5, 2000.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eitzman, D. T. Articles by Ginsburg, D. Search for Related Content PubMed PubMed Citation Articles by Eitzman, D. T. Articles by Ginsburg, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Carotid Artery Disease Hazardous Substances DB CHOLESTEROL Related Collections Lipids Coagulation and fibronolysis Platelets Animal models of human disease Pathophysiology