Scavenger Receptor Class B Type I–Mediated Protection Against Atherosclerosis in LDL Receptor–Negative Mice Involves Its Expression in Bone Marrow–Derived Cells
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.
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
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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 control13,14⇓). 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.
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 5×106 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.
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
Data were considered statistically significantly different only if P>0.05, determined by Student’s t test (Excel software).
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).
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.
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.
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.
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 cells19,33,34⇓⇓ may mediate the efflux of cholesterol to HDL19,35–37⇓⇓⇓ and suppress plaque development. Third, SR-BI may prevent accumulation of atherogenic lipoproteins in plasma.15,18⇓ Fourth, it may contribute to NO-mediated atheroprotection38–40⇓⇓ 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 hypoxia43,44⇓ (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, we15,20,21⇓⇓ and others18,22,23⇓⇓ 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 liver10–12,20,22,23⇓⇓⇓⇓⇓ may be effective for treating human atherosclerotic cardiovascular disease.
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.
This research was codirected by Bernardo Trigatti and Monty Krieger (firstname.lastname@example.org).
- Received May 9, 2003.
- Accepted June 4, 2003.
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