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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1589.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Scavenger Receptor Class B Type I–Mediated Protection Against Atherosclerosis in LDL Receptor–Negative Mice Involves Its Expression in Bone Marrow–Derived Cells

Scott D. Covey; Monty Krieger; Wei Wang; Marsha Penman; Bernardo L. Trigatti

From the Department of Biology (M.K., M.P., B.L.T.), Massachusetts Institute of Technology, Cambridge, Mass, and the Department of Biochemistry (S.D.C., W.W., B.L.T.), McMaster University, Hamilton, Ontario, Canada.

Correspondence to Bernardo L. Trigatti, Room HSC-4H35, Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. E-mail trigatt{at}mcmaster.ca

	Abstract

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Objective— Scavenger receptor class B type I (SR-BI) is a cell-surface HDL receptor that is implicated in reverse cholesterol transport and protection against atherosclerosis. We have previously demonstrated that SR-BI/apolipoprotein E double-knockout mice develop severe occlusive coronary artery disease and myocardial infarction and die at 6 weeks of age. To determine if this is a general effect of a lack of SR-BI, we generated mice deficient in both SR-BI and the LDL receptor.

Methods and Results— Complete ablation of SR-BI expression in LDL receptor knockout mice resulted in increased plasma cholesterol associated with HDL particles of abnormally large size and a 6-fold increase in diet-induced aortic atherosclerosis but no macroscopic evidence of early-onset coronary artery disease, cardiac pathology, or early death. Furthermore, selective elimination of SR-BI expression in bone marrow–derived cells resulted in increased diet-induced atherosclerosis in LDL receptor knockout mice without concomitant alterations in the distributions of plasma lipoprotein cholesterol.

Conclusions— SR-BI expression protects against atherosclerosis in LDL receptor–deficient as well as apolipoprotein E–deficient mice, and its expression in bone marrow–derived cells contributes to this protection.

Key Words: scavenger receptor class B type I • atherosclerosis • bone marrow transplant • HDL • cholesterol

	Introduction

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The accumulation of LDL cholesterol in bone marrow (BM)-derived macrophages in the artery wall and their consequent conversion into cholesterol-loaded foam cells is an early step in atherogenesis and an important cause of the epidemiological relationship between LDL and atherosclerosis.¹ The ability of HDL to protect against atherosclerosis² may involve several mechanisms, eg, protecting LDL from oxidation and efficient scavenger receptor–mediated uptake³ and regulating endothelial cell metabolism (eg, controlling endothelial NO synthase activity via scavenger receptor class B type I [SR-BI]^4,5). HDL also mediates reverse cholesterol transport (RCT)^6,7 in which cholesterol is transferred from macrophage foam cells to HDL (efflux), esterified, delivered to liver (directly from HDL or indirectly after transfer to other lipoproteins), and subsequently recycled or secreted in bile. Hepatic (and steroidogenic cell) uptake of cholesteryl esters directly from HDL involves selective lipid uptake, the net transfer of mainly neutral lipids of HDL without net uptake and degradation of its apolipoproteins.⁸

See page 1486

SR-BI mediates physiologically relevant selective HDL lipid uptake.^9–14 Hepatic SR-BI overexpression in mice drastically reduces plasma HDL cholesterol and increases biliary cholesterol levels.^10–12 Conversely, complete elimination of SR-BI in mice (null mutant) increases plasma HDL cholesterol in abnormally large HDL particles, decreases biliary cholesterol levels, and reduces lipid stores in steroidogenic tissues.^14–16 Mice with partially reduced SR-BI attributable to a promoter insertion (SR-BIatt mouse) exhibit phenotypes similar to those of heterozygous null mutants (hepatic SR-BI expression 50% of control^13,14). Analysis of these mice confirmed and extended conclusions drawn from the heterozygous and homozygous null SR-BI knockout (KO) mice.^13,14,17,18 SR-BI can also mediate efflux of unesterified cholesterol to HDL in cultured cells¹⁹; however, the physiological significance of this activity is unclear.

The critical role of SR-BI in HDL metabolism suggested that SR-BI expression levels might influence development of atherosclerosis. We and others have examined the effects of loss of SR-BI expression or hepatic SR-BI overexpression on atherosclerosis in murine models.^{15,18,20–23} For example, in young (4- to 7-week-old) apolipoprotein E (apoE) KO mice, elimination of SR-BI doubled plasma cholesterol, altered sizes and compositions of lipoproteins, and dramatically accelerated atherosclerosis.¹⁵ SR-BI/apoE double-KO (dKO) mice develop severe occlusive coronary artery disease and myocardial infarctions, exhibit reduced heart function and cardiac conductance abnormalities, and die at 6 weeks of age.²¹ These severe phenotypes were not observed in apoE KO mice heterozygous for the SR-BI–null mutation (B.L.T., A. Braun [Department of Biology, Massachusetts Institute of Technology, Cambridge], M.K., unpublished data, 2000). Nor were effects of attenuated SR-BI expression on atherosclerosis or coronary heart disease (CHD) reported in doubly homozygous SR-BIatt/apoE KO mice, whose plasma lipoproteins did not significantly differ from those of apoE KO mice.²⁴

Because of the unusual severity of disease in the SR-BI/apoE dKO mice and reports of opposing effects of some gene knockouts on atherosclerosis in different atherogenic mouse models,^25,26 we determined if complete ablation of SR-BI in LDLR (SR-BI/LDLR) KO mice fed a high-fat diet for 2 months also accelerated atherosclerosis and caused very rapid death. We observed 6-fold increased aortic atherosclerosis in these SR-BI/LDLR dKO mice relative to LDLR KO controls but no evidence of early-onset CHD and sudden death. Furthermore, we found that eliminating SR-BI in BM-derived cells in otherwise SR-BI-replete LDLR KO mice increased aortic atherosclerosis. These data support the proposal that SR-BI normally protects against atherosclerosis¹⁵ and that this is attributable, at least in part, to its expression in BM-derived cells.

	Methods

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Mice
All experiments were approved by institutional ethics committees. SR-BI/LDLR dKO and control LDLR KO mice had mixed C57BL/6:129 background. All mice used for BM transplantation (BMT) (LDLR KO recipients [Jackson Laboratories, Bar Harbor Maine], SR-BI KO, and wild-type donors) were on a C57BL/6 background.²⁷ C57BL/6 and SR-BI KO BM donor mice were given 0.5% probucol in feed (Harlan Teklad)²⁷ because of its salutary effects on reproduction in these animals.

Bone Marrow Transplantation
LDLR KO females (2 months old) were irradiated (10 Gy; ⁶⁰Co source), and male donor BM (3 to 5x10⁶ cells per mouse; Iscove’s medium containing 2% FBS, penicillin [50 U/mL], and streptomycin [50 µg/mL]) was injected intravenously (under anesthesia). One month after transplant, heparinized blood was collected for polymerase chain reaction (PCR) analysis of BM reconstitution.

PCR Genotyping
DNA was prepared from tail biopsies¹⁴ or from blood cells using the NucleoSpin Blood Quick Pure kit (BD Biosciences). Genotypes were determined by PCR.^14,21,27

Induction and Measurement of Atherosclerosis
Mice were fed an atherogenic Western diet (Dyets Inc) for 2 months beginning at age 3 months (SR-BI/LDLR dKO and control LDLR KO mice) or beginning 1 month after BMT for 4 months. Mice were fasted, and plasma and tissues were prepared.¹⁵ Hearts were visually inspected for myocardial damage suggestive of infarction, and random longitudinal sections were trichrome-stained.²¹ Aortas were Sudan IV–stained and mounted onto glass slides with glycerol-gelatin (Sigma Chemical Co), and atherosclerosis was quantified (Scion Image Software, Scion Corporation) as the percent inner aorta surface area containing Sudan IV–staining lipid.²⁸

Plasma Lipid and Lipoprotein Analysis
Plasma was fractionated by gel filtration-FPLC, and total cholesterol analyses were performed as described.¹⁴ apoAI and apoB levels were determined by quantitative immunoblotting.¹⁵

Statistical Analysis
Data were considered statistically significantly different only if P>0.05, determined by Student’s t test (Excel software).

	Results

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Atherosclerosis in Fat-Fed SR-BI/LDLR dKO Mice
SR-BI/LDLR dKO mice appeared healthy regardless of diet and did not exhibit increased mortality up to 5 months of age (2 months on Western diet) compared with LDLR single-KO controls (not shown). Plasma total cholesterol in SR-BI/LDLR dKO mice was 1.7-fold higher than in LDLR KO controls fed low-fat diet (Table), attributable mainly to increased cholesterol in abnormally large HDL-sized particles (Figure 1A; HDL peak shifted to the left in the lipoprotein cholesterol profile [•] relative to that in the LDLR KO control []). Similar changes are seen in SR-BI single-KO mice (2.2-fold increased plasma cholesterol associated with abnormally large HDL particles¹⁴). Surprisingly, after 2 months of high-fat feeding, plasma total cholesterol levels in the SR-BI/LDLR dKO mice were lower (Table), even though the HDL-sized particles from the dKO mice were larger and contained 3 times more total cholesterol than those of LDLR KO controls (Figure 1B and Table). The reduced plasma total cholesterol was attributable to reduced cholesterol in IDL/LDL-size lipoproteins and associated with reduced plasma apoB (Figure 1B and Table).

View this table: [in this window] [in a new window]   Analysis of Plasma Lipoproteins and Atherosclerosis in SR-BI/LDLR dKO and Control LDLR KO Mice Fed a High-Fat Diet for 2 Months

View larger version (28K): [in this window] [in a new window]   Figure 1. Plasma lipoprotein total cholesterol profiles from SR-BI/LDLR dKO and control LDLR KO mice. Lipoproteins from plasma samples from SR-BI/LDLR dKO (•) and control LDLR KO mice ( were size-fractionated by gel filtration–FPLC and the concentration of total cholesterol in each fraction measured. A, Low-fat chow diet. B, High-fat Western-type diet (2 months). Representative profiles from individual mice are shown.

SR-BI/LDLR dKO mice fed the high-fat diet for 2 months had 6-fold increased aortic atherosclerosis (Table and Figure 2; 24±4% coverage) versus LDLR KO controls (3.9±1.6% coverage, P=0.00001). The data in Figures 1 and 2 and the Table were from female mice; qualitatively similar effects were observed in males (not shown). Thus, SR-BI expression protects against atherosclerosis in Western diet–fed LDLR KO mice.

View larger version (39K): [in this window] [in a new window]   Figure 2. Atherosclerosis in aortas from SR-BI/LDLR dKO and control LDLR KO mice. Atherosclerosis in aortas was visualized by Sudan IV staining of entire fixed aortas. Representative images of aortas from control LDLR KO (top) and SR-BI/LDLR dKO (bottom) mice are shown.

SR-BI/apoE dKO mice fed a low-fat diet develop accelerated atherosclerosis, early-onset occlusive coronary artery disease, and extensive myocardial infarction and die at 6 weeks of age.²¹ In contrast, SR-BI/LDLR dKO mice fed the high-fat diet for 2 months appeared healthy, and their hearts appeared normal (no characteristic macroscopic lesions or myocardial fibrosis [trichrome staining, not shown] as seen in SR-BI/apoE dKO mice²¹).

Atherosclerosis in LDLR KO Mice With BM-Specific SR-BI Deficiency
To determine if SR-BI expression in macrophages and other BM-derived cells influences atherogenesis in LDLR KO mice, we used BMT to generate LDLR KO mice with SR-BI selectively disrupted in BM-derived cells. Here, all mice (wild-type, SR-BI KO [with normal LDLR genes], and LDLR KO) had a pure C57BL/6 background to facilitate detection of subtle differences in atherosclerosis from BM cell-specific alterations in SR-BI expression. LDLR-positive SR-BI KO and wild-type control mice were BM donors, and lethally irradiated LDLR KO mice were recipients. Transplantation resulted in an intact LDLR gene in BM-derived cells in all mice. This has no effect on diet-induced atherosclerosis in LDLR KO mice.^29–31 One month after transplantation, most circulating blood cells contained the mutant SR-BI allele (online Figure, lanes 6 and 7 versus 4 and 5; see http://atvb.ahajournals.org) and normal LDLR alleles (not shown) when BM-donors were SR-BI KO. Thus, there was a high degree of repopulation with donor-derived BM in all of the recipient mice.

Plasma total cholesterol levels and lipoprotein total cholesterol profiles (Figure 3) from LDLR KO mice with SR-BI KO versus wild-type donor BM were similar on normal chow (1 month after BMT, not shown) and high-fat (4 months) diets (1170±440 mg/dL, n=6, versus 1210±370 mg/dL, n=5 for mice transplanted with SR-BI KO versus wild-type BM) (online table, available at http://atvb.ahajournals.org). Thus, SR-BI expression in BM-derived cells (including monocyte-derived macrophages) did not play a significant role in determining plasma cholesterol levels or the structures of circulating lipoproteins.

View larger version (24K): [in this window] [in a new window]   Figure 3. Plasma lipoprotein total cholesterol profiles from LDLR KO mice transplanted with BM from either wild-type or SR-BI KO donors. LDLR KO mice transplanted with BM from wild-type () or SR-BI KO (•) donors were fed a Western-type diet beginning 1 month after transplantation for a total of 4 months. Plasma from 3 to 4 mice was pooled, plasma lipoproteins were separated by size by gel filtration-FPLC, and the concentration of total cholesterol in each fraction was measured.

After 4 months on the Western diet, most aortic atherosclerotic plaque was found in the aortic arch of LDLR KO mice regardless of the BM donor. LDLR KO mice with SR-BI KO BM had 1.7-fold more atherosclerosis in the aortic arch than those receiving wild-type BM (Figure 4A, P=0.012). Mice with SR-BI KO BM had 1.5-fold higher atherosclerosis over the entire aorta than those with wild-type BM (Figure 4B P=0.017); however, the increased atherosclerosis in the descending aorta was not statistically significant (P=0.23). Therefore, normal SR-BI expression in BM-derived cells contributes significantly to protection against diet-induced aortic atherosclerosis in LDLR KO mice.

View larger version (26K): [in this window] [in a new window]   Figure 4. Atherosclerosis in LDLR KO mice transplanted with BM from either wild-type or SR-BI KO donors. One month after transplantation with BM from wild-type ( or SR-BI KO (•) donors, mice were fed a high-fat Western diet for an additional 4 months. Atherosclerosis was then measured as the percentage of the inner wall of the aortic arch (A) or entire aorta (B) occupied by Sudan IV staining lipid-rich plaques. Each point represents an individual animal. The horizontal bars represent the mean values (average±SD), which were as follows: A, 12.1±4.5% and 20.1±5.2% coverage, P=0.012 (indicated by **); B, 3.7±1.0% and 5.4±1.1%, P=0.017 (indicated by *) for BM from wild-type (n=5) or SR-BI KO donors (n=6), respectively.

	Discussion

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Fat-fed SR-BI/LDLR dKO mice exhibited increased (515%) atherosclerosis relative to LDLR KO controls. This is consistent with the more modest 69% to 171% increase in diet-induced aortic root atherosclerosis in SR-BIatt/LDLR KO mice.¹⁸ The fat-fed SR-BIatt/LDLR KO mice had increased LDL cholesterol without significant alterations in HDL cholesterol levels, suggesting that impaired LDL cholesterol clearance may have accounted for the increased atherosclerosis relative to LDLR KO mice.¹⁸ In contrast, fat-fed SR-BI/LDLR dKO mice (this study, Figure 1 and Table 1) had lower cholesterol and apoB associated with LDL-sized lipoproteins and increased cholesterol associated with large HDL. This suggests that impaired HDL cholesterol clearance likely played a critical role in the development of atherosclerosis in the complete absence of SR-BI expression. We also observed dramatically reduced apoB in IDL/LDL fractions and increased cholesterol in abnormally large HDL in SR-BI/apoE dKO (versus apoE KO controls).¹⁵ The mechanisms underlying the reduced plasma apoB and IDL/LDL cholesterol are not clear; however, they may reflect alterations in secretion of apoB-containing lipoproteins, possibly as a consequence of altered hepatic uptake of HDL cholesterol.³²

This study supports others showing that normal expression of SR-BI protects against atherosclerosis.^15,20,22,23 This protection may involve any one or a combination of mechanisms. First, SR-BI mediates hepatic uptake and biliary secretion of HDL-cholesterol and therefore may stimulate reverse cholesterol transport.^{7,9,10,13,15,16} Second, its expression in BM-derived macrophage foam cells^19,33,34 may mediate the efflux of cholesterol to HDL^19,35–37 and suppress plaque development. Third, SR-BI may prevent accumulation of atherogenic lipoproteins in plasma.^15,18 Fourth, it may contribute to NO-mediated atheroprotection^38–40 by mediating HDL-dependent endothelial NO synthase activation in vascular endothelium.^4,5 Fifth, SR-BI expression may influence expression of other atherogenic/atheroprotective genes in the artery wall.⁴¹ Sixth, SR-BI expression can influence reticulocyte maturation⁴² and thus could protect against atherosclerosis by preventing anemia and artery wall hypoxia^43,44 (for alternate view, see the study by Paul et al⁴⁵).

To determine the influence on atherosclerosis of SR-BI expression in BM-derived cells, we used BMT.^{29–31,46–53} Elimination of SR-BI from BM-derived cells increased atherosclerosis 1.7-fold in aortic arches of LDLR KO mice fed a high-fat diet for 4 months. This effect is striking; in comparison, BM-specific elimination of ABCA1, a key component of the cholesterol efflux pathway,^54,55 gives a 1.6- to 3-fold increase in diet-induced atherosclerosis in apoE or LDLR KO mice.^52,53 Thus, SR-BI expression in these cells seems to contribute to the ability of SR-BI to protect against atherosclerosis, possibly because of its influence on cellular cholesterol efflux. Initial attempts to assess the in vitro importance of SR-BI for macrophage cholesterol metabolism by comparing cholesterol efflux from peritoneal macrophages derived from wild-type and SR-BI KO mice were uninformative. Cellular cholesterol efflux rates were virtually identical, probably because SR-BI expression in wild-type and SR-BI KO peritoneal macrophages was too low to be detected by sensitive immunoblotting of total cell membranes (not shown). SR-BI expression in BM-derived cells clearly does not account for all of the protective effect of SR-BI, because elimination of SR-BI from all tissues in the dKO mice resulted in a much greater, 6-fold increase in atherosclerosis in mice fed a Western diet for 2 months. Clearly, SR-BI expression in other tissues, especially the liver, which has a profound influence on lipoprotein metabolism, also plays an important atheroprotective role.²⁰

Fat-fed SR-BI/LDLR dKO mice exhibit red blood cell morphological alterations (irregular shape and large inclusions, not shown) seen in SR-BI/apoE dKO mice fed a normal low-fat diet and attributed to cholesterol-dependent impaired maturation.⁴² Abnormal morphology was not observed in fat-fed LDLR KO mice transplanted with SR-BI KO or wild-type BM or untransplanted LDLR KO mice [not shown]. Thus, impaired red cell maturation did not contribute to the increased atherosclerosis in mice with BM-specific SR-BI gene disruption.

Unlike the 5- to 8-week-old SR-BI/apoE dKO mice fed a low-fat diet,^15,21 SR-BI/LDLR dKO mice fed a Western diet for 2 months did not exhibit evidence of myocardial infarctions (macroscopic observation of hearts and microscopic analysis of trichrome-stained sections, not shown) or premature death. Thus, SR-BI/LDLR dKO mice apparently differ from the SR-BI/apoE dKO mice that rapidly develop many distinctive characteristics of human CHD.²¹ It remains to be determined if occlusive CAD and myocardial fibrosis will develop in SR-BI/LDLR dKO mice maintained on the Western diet for longer periods of time. The precise mechanisms by which apoE deficiency in the SR-BI KO background causes early-onset CHD are not yet clear.²¹

In summary, we^15,20,21 and others^18,22,23 have demonstrated that SR-BI plays an important role in protecting against atherosclerosis in distinct mouse models. We have also demonstrated for the first time that the mechanisms of atheroprotection include SR-BI expression in BM-derived cells. These findings raise the possibility that strategies aimed at stimulating SR-BI expression or activity in these cells, potentially independently of altering lipoprotein metabolism, as well as stimulating SR-BI activity in the liver^{10–12,20,22,23} may be effective for treating human atherosclerotic cardiovascular disease.

	Acknowledgments

 
This work was supported by grants HL64737 and HL66105 from the United States National Institutes of Health Heart Lung and Blood Institute to M.K. and by grants from the Canadian Institutes of Health Research, Canada Foundation for Innovation, and the Ontario Innovation Trust and the William T. McEachern Fellowship Fund University of Toronto to B.L.T. B.L.T. is a Heart and Stroke Foundation of Canada New Investigator. The authors gratefully acknowledge Elizabeth Alcamo, Tomas Baumgartner, Anne Braun, Mike Butler, Shamsah Ebrahim, Herman Eisen, Susan Erdman, Kairbaan Hodivala-Dilke, Richard Hynes, Hussein Kanji, Robert Pasuta, Ali Rizvi, Stephen Robinson, and Ayce Yesilaltay for helpful discussions, access to equipment, and expert technical assistance.

	Footnotes

 
This research was codirected by Bernardo Trigatti and Monty Krieger (krieger@mit.edu).

Received May 9, 2003; accepted June 4, 2003.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Pentikainen MO, Oorni K, Ala-Korpela M, Kovanen PT. Modified LDL: trigger of atherosclerosis and inflammation in the arterial intima. J Intern Med. 2000; 247: 359–370.[CrossRef][Medline] [Order article via Infotrieve]
2. Gordon DJ, Rifkind BM. High-density lipoprotein: the clinical implications of recent studies. N Engl J Med. 1989; 321: 1311–1316.[Medline] [Order article via Infotrieve]
3. Banka CL. High density lipoprotein and lipoprotein oxidation. Curr Opin Lipidol. 1996; 7: 139–142.[Medline] [Order article via Infotrieve]
4. Li XA, Titlow WB, Jackson BA, Giltiay N, Nikolova-Karakashian M, Uittenbogaard A, Smart EJ. High density lipoprotein binding to scavenger receptor, class B, type I activates endothelial nitric-oxide synthase in a ceramide-dependent manner. J Biol Chem. 2002; 277: 11058–11063.[Abstract/Free Full Text]
5. Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME, Hobbs HH, Shaul PW. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med. 2001; 7: 853–857.[CrossRef][Medline] [Order article via Infotrieve]
6. Glomset JA. The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res. 1968; 9: 155–167.[Abstract]
7. Rigotti A, Trigatti B, Babitt J, Penman M, Xu S, Krieger M. Scavenger receptor BI: a cell surface receptor for high density lipoprotein. Curr Opin Lipidol. 1997; 8: 181–188.[CrossRef][Medline] [Order article via Infotrieve]
8. Glass C, Pittman RC, Weinstein DB, Steinberg D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc Natl Acad Sci U S A. 1983; 80: 5435–5439.[Abstract/Free Full Text]
9. Krieger M. Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI. Annu Rev Biochem. 1999; 68: 523–558.[CrossRef][Medline] [Order article via Infotrieve]
10. Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature. 1997; 387: 414–417.[CrossRef][Medline] [Order article via Infotrieve]
11. Wang N, Arai T, Ji Y, Rinninger F, Tall AR. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice. J Biol Chem. 1998; 273: 32920–32926.[Abstract/Free Full Text]
12. Ueda Y, Royer L, Gong E, Zhang J, Cooper PN, Francone O, Rubin EM. Lower plasma levels and accelerated clearance of high density lipoprotein (HDL) and non-HDL cholesterol in scavenger receptor class B type I transgenic mice. J Biol Chem. 1999; 274: 7165–7171.[Abstract/Free Full Text]
13. Varban ML, Rinninger F, Wang N, Fairchild-Huntress V, Dunmore JH, Fang Q, Gosselin ML, Dixon KL, Deeds JD, Acton SL, Tall AR, Huszar D. Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol. Proc Natl Acad Sci U S A. 1998; 95: 4619–4624.[Abstract/Free Full Text]
14. Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A. 1997; 94: 12610–12615.[Abstract/Free Full Text]
15. Trigatti B, Rayburn H, Vinals M, Braun A, Miettinen H, Penman M, Hertz M, Schrenzel M, Amigo L, Rigotti A, Krieger M. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc Natl Acad Sci U S A. 1999; 96: 9322–9327.[Abstract/Free Full Text]
16. Mardones P, Quinones V, Amigo L, Moreno M, Miquel JF, Schwarz M, Miettinen HE, Trigatti B, Krieger M, VanPatten S, Cohen DE, Rigotti A. Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. J Lipid Res. 2001; 42: 170–180.[Abstract/Free Full Text]
17. Ji Y, Wang N, Ramakrishnan R, Sehayek E, Huszar D, Breslow JL, Tall AR. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J Biol Chem. 1999; 274: 33398–33402.[Abstract/Free Full Text]
18. Huszar D, Varban ML, Rinninger F, Feeley R, Arai T, Fairchild-Huntress V, Donovan MJ, Tall AR. Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler Thromb Vasc Biol. 2000; 20: 1068–1073.[Abstract/Free Full Text]
19. Ji Y, Jian B, Wang N, Sun Y, Moya ML, Phillips MC, Rothblat GH, Swaney JB, Tall AR. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem. 1997; 272: 20982–20985.[Abstract/Free Full Text]
20. Kozarsky KF, Donahee MH, Glick JM, Krieger M, Rader DJ. Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol. 2000; 20: 721–727.[Abstract/Free Full Text]
21. Braun A, Trigatti BL, Post MJ, Sato K, Simons M, Edelberg JM, Rosenberg RD, Schrenzel M, Krieger M. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ Res. 2002; 90: 270–276.[Abstract/Free Full Text]
22. Arai T, Wang N, Bezouevski M, Welch C, Tall AR. Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J Biol Chem. 1999; 274: 2366–2371.[Abstract/Free Full Text]
23. Ueda Y, Gong E, Royer L, Cooper PN, Francone OL, Rubin EM. Relationship between expression levels and atherogenesis in scavenger receptor class B, type I transgenics. J Biol Chem. 2000; 275: 20368–20373.[Abstract/Free Full Text]
24. Arai T, Rinninger F, Varban L, Fairchild-Huntress V, Liang CP, Chen W, Seo T, Deckelbaum R, Huszar D, Tall AR. Decreased selective uptake of high density lipoprotein cholesteryl esters in apolipoprotein E knock-out mice. Proc Natl Acad Sci U S A. 1999; 96: 12050–12055.[Abstract/Free Full Text]
25. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashima Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Kodama T, et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997; 386: 292–296.[CrossRef][Medline] [Order article via Infotrieve]
26. de Winther MP, Gijbels MJ, van Dijk KW, van Gorp PJ, Suzuki H, Kodama T, Frants RR, Havekes LM, Hofker MH. Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice. Atherosclerosis. 1999; 144: 315–321.[CrossRef][Medline] [Order article via Infotrieve]
27. Miettinen HE, Rayburn H, Krieger M. Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. J Clin Invest. 2001; 108: 1717–1722.[CrossRef][Medline] [Order article via Infotrieve]
28. Tangirala RK, Rubin EM, Palinski W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res. 1995; 36: 2320–2328.[Abstract]
29. Linton MF, Babaev VR, Gleaves LA, Fazio S. A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation. J Biol Chem. 1999; 274: 19204–19210.[Abstract/Free Full Text]
30. Boisvert WA, Spangenberg J, Curtiss LK. Role of leukocyte-specific LDL receptors on plasma lipoprotein cholesterol and atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 1997; 17: 340–347.[Abstract/Free Full Text]
31. Herijgers N, Van Eck M, Groot PH, Hoogerbrugge PM, Van Berkel TJ. Effect of bone marrow transplantation on lipoprotein metabolism and atherosclerosis in LDL receptor-knockout mice. Arterioscler Thromb Vasc Biol. 1997; 17: 1995–2003.[Abstract/Free Full Text]
32. Sniderman AD, Zhang Z, Genest J, Cianflone K. Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells. J Lipid Res. 2003; 44: 527–532.[Abstract/Free Full Text]
33. Hirano K, Yamashita S, Nakagawa Y, Ohya T, Matsuura F, Tsukamoto K, Okamoto Y, Matsuyama A, Matsumoto K, Miyagawa J, Matsuzawa Y. Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions. Circ Res. 1999; 85: 108–116.[Abstract/Free Full Text]
34. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation. 2000; 101: 2411–2417.[Abstract/Free Full Text]
35. Stangl H, Cao G, Wyne KL, Hobbs HH. Scavenger receptor, class B, type I-dependent stimulation of cholesterol esterification by high density lipoproteins, low density lipoproteins, and nonlipoprotein cholesterol. J Biol Chem. 1998; 273: 31002–31008.[Abstract/Free Full Text]
36. Jian B, de la Llera-Moya M, Ji Y, Wang N, Phillips MC, Swaney JB, Tall AR, Rothblat GH. Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors. J Biol Chem. 1998; 273: 5599–5606.[Abstract/Free Full Text]
37. Huang ZH, Mazzone T. ApoE-dependent sterol efflux from macrophages is modulated by scavenger receptor class B type I expression. J Lipid Res. 2002; 43: 375–382.[Abstract/Free Full Text]
38. Shaul PW. Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol. 2002; 64: 749–774.[CrossRef][Medline] [Order article via Infotrieve]
39. Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric Oxide. 2001; 5: 88–97.[CrossRef][Medline] [Order article via Infotrieve]
40. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997; 48: 489–509.[CrossRef][Medline] [Order article via Infotrieve]
41. Van Eck M, Twisk J, Hoekstra M, Van Rij BT, Van Der Lans CA, Bos IS, Kruijt JK, Kuipers F, Van Berkel TJ. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and the liver. J Biol Chem. 2003; 14: 14.
42. Holm TM, Braun A, Trigatti BL, Brugnara C, Sakamoto M, Krieger M, Andrews NC. Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI. Blood. 2002; 99: 1817–1824.[Abstract/Free Full Text]
43. Gainer JL. Hypoxia and atherosclerosis: re-evaluation of an old hypothesis. Atherosclerosis. 1987; 68: 263–266.[CrossRef][Medline] [Order article via Infotrieve]
44. Pasterkamp G, Virmani R. The erythrocyte: a new player in atheromatous core formation. Heart. 2002; 88: 115–116.[Free Full Text]
45. Paul A, Calleja L, Vilella E, Martinez R, Osada J, Joven J. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice with phenylhydrazine-induced anemia. Atherosclerosis. 1999; 147: 61–68.[CrossRef][Medline] [Order article via Infotrieve]
46. Linton MF, Atkinson JB, Fazio S. Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science. 1995; 267: 1034–1037.[Abstract/Free Full Text]
47. Boisvert WA, Spangenberg J, Curtiss LK. Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. J Clin Invest. 1995; 96: 1118–1124.
48. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA, Atkinson JB, Linton MF. Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci U S A. 1997; 94: 4647–4652.[Abstract/Free Full Text]
49. Boisvert WA, Curtiss LK. Elimination of macrophage-specific apolipoprotein E reduces diet-induced atherosclerosis in C57BL/6J male mice. J Lipid Res. 1999; 40: 806–813.[Abstract/Free Full Text]
50. Linton MF, Fazio S. Macrophages, lipoprotein metabolism, and atherosclerosis: insights from murine bone marrow transplantation studies. Curr Opin Lipidol. 1999; 10: 97–105.[CrossRef][Medline] [Order article via Infotrieve]
51. Van Eck M, Herijgers N, Vidgeon-Hart M, Pearce NJ, Hoogerbrugge PM, Groot PH, Van Berkel TJ. Accelerated atherosclerosis in C57Bl/6 mice transplanted with ApoE-deficient bone marrow. Atherosclerosis. 2000; 150: 71–80.[CrossRef][Medline] [Order article via Infotrieve]
52. Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, Coskran T, Haghpassand M, Francone OL. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol. 2002; 22: 630–637.[Abstract/Free Full Text]
53. van Eck M, Bos IS, Kaminski WE, Orso E, Rothe G, Twisk J, Bottcher A, Van Amersfoort ES, Christiansen-Weber TA, Fung-Leung WP, Van Berkel TJ, Schmitz G. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc Natl Acad Sci U S A. 2002; 99: 6298–6303.[Abstract/Free Full Text]
54. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Hayden MR, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
55. Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999; 104: R25–R31.

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