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CD36 has been shown to play a role in atherosclerosis in the apolipoprotein E knockout (apoEo) mouse. We observed no difference in aortic lesion area between Western diet (WD) fed LDLRo and LDLRo/CD36o mice. The objective was to understand the mechanism of CD36-dependent atherogenesis.
ApoEo mice transplanted with bone marrow from LDLRo/CD36o mice had significantly less aortic lesion compared with those transplanted with LDLRo marrow. Reciprocal macrophage transfer into hyperlipidemic apoEo and LDLRo showed that foam cell formation induced by in vivo modified lipoproteins was dependent on the lipoprotein, not macrophage type. LDLRo and LDLRo/CD36o mice were fed a cholesterol enriched diet (HC) and we now observed significant lesion inhibition in LDLRo/CD36o mice. LDL/plasma isolated from HC fed LDLRo mice induced significantly greater jnk phosphorylation, cytokine release and reactive oxygen species secretion than LDL/plasma from WD fed LDLRo mice, and this was CD36-dependent. HC fed LDLRo mice had higher circulating levels of cytokines than WD fed mice.
These data support the hypothesis that CD36-dependent atherogenesis is contingent upon a pro-inflammatory milieu that promotes the creation of specific CD36 ligands, not solely hypercholesterolemia, and may explain the greater degree/accelerated rate of atherosclerosis observed in syndromes associated with inflammatory risk.
A critical step in atherosclerotic lesion formation is the accumulation of macrophage-derived cholesterol laden foam cells in the vessel wall (1). Foam cell formation is dependent on recognition and internalization of low density lipoprotein (LDL) particles that become trapped and modified in the intima in response to inflammatory stimuli (1, 2). We and others have identified the type B scavenger receptor CD36 as a major macrophage receptor for oxidized LDL, particularly LDL particles modified by a vessel wall oxidizing system that includes leukocyte myeloperoxidase and nitric oxide (3–9). Macrophages from CD36o mice are deficient in their capacity to form foam cells in vitro (4, 9), and in vivo (10), and we have found that CD36o mice bred into the pro-atherogenic apoEo background are significantly protected from developing atherosclerosis (5, 6, 11, 12), although this has been observed to a lesser extent by another group (13). They found significant lesion inhibition in the aortic tree of female apoEo/CD36o mice and a trend towards less lesion in the aortic tree of male apoEo/CD36o mice (13).
ApoEo and LDLRo mice (C57Bl/6) are the two most widely used models of atherosclerosis (14–17). Although often used interchangeably, they differ profoundly. ApoE is a component of chylomicron remnants, intermediate density lipoproteins, very low density lipoproteins (VLDL), β-migrating VLDL and high density lipoproteins (HDL) (14–16). Absence of apoE results in impaired uptake of remnant lipoproteins by the LDL receptor and the LDL receptor related protein (16). ApoEo mice fed normal chow (NC) exhibit hyperlipidemia and develop atherosclerotic lesions that resemble human lesions both morphologically and in terms of anatomical localization (14, 15). Atherogenesis is exacerbated by diets rich in certain fats and/or added cholesterol (16). NC fed LDLRo mice also exhibit hyperlipidemia, but the particle that accumulates in plasma is LDL and mice do not develop significant atherosclerotic lesions (17, 18).
LDLRo mice fed either NC or WD (no cholate, 20% saturated fat, 0.2% cholesterol) have a greater proportion of their total plasma cholesterol in the HDL fraction compared with apoEo mice (17, 18). The protective effect of this lipoprotein may account in part for the absence of lesion in NC fed, yet hyperlipidemic, LDLRo mice. Another difference between the two models relates to inflammation. Antibodies against epitopes carried by the aberrant lipoprotein have been identified in plasma of apoEo mice (19, 20). These epitopes are also found on in vitro oxidatively modified LDL, and in human atherosclerotic lesions (21) and imply a chronic pro-oxidant stress and a chronic pro-inflammatory response. These antibodies are produced minimally in LDLRo mice, perhaps related to the anti-oxidant and anti-inflammatory activities of HDL and/or the pro-inflammatory properties of the circulating remnant particles in the apoEo (19, 22, 23). The composition of LDL isolated from LDLRo mice is relatively less atherogenic when compared with lipoprotein isolated from apoEo mice, containing less triacylglycerol and less cholesterol/cholesterol ester, and significantly fewer oxidized lipids when compared with lipoprotein isolated from apoEo mice (24). Additionally, LDL from LDLRo mice is not as good ligand for CD36 or scavenger receptor A (SRA)-I/II, and has considerably less ability to promote foam cell formation in vitro (24).
Because recognition of modified LDL by CD36 is dependent on the presence of specific oxidized phospholipid species, we hypothesized that CD36o mice bred into the LDLRo background would respond differently to WD feeding than those bred into the apoEo background. We report here that CD36 gene inactivation did not confer protection from atherosclerosis in WD fed LDLRo mice unless the diet was modified by inclusion of high cholesterol. Our data from macrophage transfer experiments, bone marrow transplantation and high cholesterol feeding suggest that differences in the pro-inflammatory milieu directly relates to CD36-dependent atherogenesis. This conclusion is supported by in vitro examination of macrophage responses. These results better define physiologically relevant environmental influences on CD36-dependent processes.
LDLRo/CD36o and LDLRo mice were derived as littermate lines from a cross between CD36o and LDLRo mice (99.225% C57Bl/6j, 0.775% 129Svj). Mice were weaned at 4 weeks of age and fed special diets for 12 weeks. Atherosclerosis morphometry, glucose tolerance testing and plasma analyses were as previously described (5, 6). IL-1α, tumor necrosis factor (TNF) α and soluble vascular cell adhesion molecule-1 (VCAM-1) were measured with murine specific ELISAs (Quantikine, R&D Systems). Other cytokines were measured in pooled plasma using a cytokine array (Mouse Cytokine/Chemokine Lincoplex Kit, Linco Research). Measurement of macrophage oxidative burst was performed using Fc OxyBURST Green assay reagent (Molecular Probes). Detailed methods are available in a supplemental file. Please see http://atvb.ahajournals.org.
Results are expressed as mean ± S.E., and statistical analyses were performed using Student’s t test for groups of 2 and ANOVA followed by Newman-Keuls multiple comparison test for groups greater than 2. In the case of aortic lesion area, the Mann-Whitney test was used. Significance was set at p<0.05.
En face analysis of aortae revealed no difference in lesion area in WD fed LDLRo mice compared with LDLRo/CD36o mice (Figure 1A, B). The absence of protection in LDLRo/CD36o mice was in spite of improvement in pro-atherogenic metabolic parameters in CD36o mice (Table I, supplement. Please see http://atvb.ahajournals.org.). For example, at sacrifice, LDLRo/CD36o mice weighed significantly less, LDLRo/CD36o male mice had significantly lower cholesterol levels and increased HDL. Fasting glucose was significantly elevated in LDLRo vs. LDLRo/CD36o mice after diet intervention and glucose tolerance testing (Figures 1C, 1D) showed a significant increase in area under the curve for LDLRo mice compared with LDLRo/CD36o mice (p<0.005). Examination of aortic sinus lesions (n = 14–21/group) revealed no difference in degree of acellularity (necrosis/apoptosis), and no difference in degree of cellularity (non-foam cell) when comparing LDLRo and LDLRo/CD36o mice of the same gender (Please see supplemental Figure I, http://atvb.ahajournals.org). However, there was significantly greater area of oil red O staining (primarily macrophage foam cells) in lesions of LDLRo males (56.02 ± 2.85%, n = 14) compared with LDLRo/CD36o males (47.62 = 2.47%, n = 19; p<0.05); lesions from female mice did not differ. A decrease in macrophage number was previously observed in lesions from apoEo/CD36o mice (13).
To examine the ability of LDLRo macrophages to undergo foam cell formation in the presence of modified LDL in vitro, elicited macrophages were incubated with copper sulfate oxidized LDL (oxLDL), or LDL modified by reactive nitrogen species generated by the leukocyte myeloperoxidase system (NO2LDL) (50 ug/ml) for 4 and 16 hours. Cells were fixed and stained with oil red O. As shown in Figure 2A, B, macrophages from LDLRo mice accumulated lipid and formed foam cells in response to both ligands, and this was markedly diminished in cells from LDLRo/CD36o mice. 36% and 82% fewer foam cells formed in response to NO2LDL in LDLRo/CD36o vs. LDLRo macrophage cultures at 4 hours and 16 hours respectively (p<0.05). 53% and 80% fewer foam cells formed in response to oxLDL in LDLRo/CD36o vs. LDLRo macrophage cultures at 4 hours and 16 hours respectively (p<0.05).
To determine if there were differences in macrophage responses, elicited macrophages were harvested from LDLRo and LDLRo/CD36o mice, and then infused into the peritoneal cavity of hyperlipidemic male apoEo mice (WD fed for 8 weeks). Three days later, macrophages were collected and stained with oil red O (10, 25, 26). As shown in Figure 3A, there was a 46.9% decrease in foam cell formation in macrophages from LDLRo/CD36o as compared with macrophages from LDLRo mice (21.04 ± 0.58% vs. 44.85 ± 1.37%, n = 4/group, p<0.0001). In the reciprocal experiment, apoEo and apoEo/CD36o macrophages were infused into the peritoneal cavities of WD fed LDLRo mice. As shown in Figure 3B, there was no difference in foam cell formation (47.44 ± 2.4% vs. 47.38 ± 1.1%, n = 3/group, p=0.98). These studies indicate that LDLRo/CD36o macrophages behave similarly to apoEo/CD36o macrophages in that they accumulate significantly less lipid compared with respective CD36 wild type control macrophages in the setting of lipoprotein that is a ligand for CD36.
To determine physiologic relevance, we transplanted hematopoietic stem cells from LDLRo or LDLRo/CD36o mice into apoEo mice. As expected, because these stem cells express apoE, total plasma cholesterol was significantly reduced when compared with mice receiving apoEo stem cells (LDLRo: 201.7 ± 12.94 mg/dL; LDLRo/CD36o: 207 ± 37.62 mg/dL; apoEo: 688.6 ± 45.51 mg/dL). There were no significant differences in plasma triacylglyceride and non-esterified fatty acid levels or insulin resistance between mice receiving stem cells from LDLRo or LDLRo/CD36o mice (data not shown). However, apoEo mice receiving LDLRo/CD36o stem cells had 38.4% less lesion area compared to those receiving LDLRo stem cells (Figure 4, 2.73 ± 0.53% vs. 4.42 ± 0.62%, n = 15/group, p<0.05).
Diets rich in cholesterol have been shown to increase the propensity for atherosclerosis in mice (18) as a result of a more pro-inflammatory milieu (27). To determine if increasing inflammation, by increasing the cholesterol content of the diet, had an effect on CD36-mediated atherosclerosis in the LDLRo, we fed 4 week old LDLRo and LDLRo/CD36o mice a high fat diet containing 1.125% cholesterol (HC). LDLRo mice, as in the case of the WD, were significantly heavier at sacrifice than LDLRo/CD36o mice (Table II, supplement. Please see http://atvb.ahajournals.org.). There were no significant differences in total cholesterol in male mice, but LDLRo female mice had total cholesterols that were lower than LDLRo/CD36o mice. HDL cholesterol and triacylglycerol were similar between gender matched groups (Table II, supplement. Please see http://atvb.ahajournals.org.). With the exception of LDLRo/CD36o females, HDL cholesterol was similar in percent of total cholesterol compared with that in WD fed mice. LDLRo/CD36o females had about 47% less cholesterol in the HDL fraction compared with their WD fed counterparts. We again observed significantly higher fasting glucose values for both LDLRo males and females, and significant increases in area under the curve in glucose tolerance testing (data not shown). As shown in Figure 5A, B, we observed a statistically significant 30.1% (10.54% ± 0.46 (n = 15) vs. 15.07% ± 1.04, (n = 15), p<0.001) and 32.4% (9.11% ± 0.83 (n = 18) vs. 13.48 ± 1.17, (n = 17), p<0.05) decrease in aortic lesion area in male and female LDLRo/CD36o mice, respectively.
The HC diet was chosen for the above study because it is a common enriched cholesterol diet used in many atherosclerosis studies in the literature. However, to rule out potential differences unrelated to cholesterol content between this diet and the WD, we did a second study with male mice using an exact version of the WD with 1.25% cholesterol (Harlan Teklad TD 96121) (Figure 5C). We observed a 56.9% decrease in aortic lesion area in LDLRo/CD36o mice compared with LDLRo mice (4.08% ± 0.81 (n = 8) vs. 9.45% ± 1.4 (n = 10), p<0.005).
Morphologic examination of lesions in the aortic sinus revealed a significant increase in oil red O staining in male LDLRo mice compared with male LDLRo/CD36o mice (n = 18/group) (Supplemental Figure II. Please see http://atvb.ahajournals.org.). This is consistent with previous data demonstrating fewer macrophages in apoEo/CD36o aortic sinus lesions (13), and data demonstrating a potential role for CD36 in macrophage migration and trapping by modified lipoproteins in lesions (28, 29). Further, as noted in aortic sinus lesions of female apoEo/CD36o (13), we found a significant increase in areas of acellularity, necrosis/apoptosis in lesions of LDLRo/CD36o male mice (Supplemental Figure II. Please see http://atvb.ahajournals.org.).
To further understand the role of the different lipoproteins, we isolated plasma from HC and WD fed LDLRo mice. After incubation with 50 and 100 ug/ml for 30 minutes, wild type and CD36o macrophages were assessed for phosphorylation of c-jun N-terminal kinase (jnk), which is essential to CD36 mediated modified LDL uptake and foam cell formation (10). As shown in Figure 6, there was ~1.5 fold greater jnk phosphorylation in macrophages incubated with plasma from HC fed mice compared with WD fed mice in wild type macrophages, and this was a CD36-dependent effect, since an increase in phosphorylation of jnk was not observed in CD36o macrophages incubated with plasma from WD and HC fed mice. We next isolated macrophages from mice fed the HC or WD and exposed them to oxLDL (50 ug/ml, overnight) to assess inflammatory response. Macrophages from HC fed LDLRo mice secreted 1.5 fold more IL-1α than those fed the WD (1586 ± 103 vs. 1063 ± 33.9 pg/mg protein, p<0.05). Macrophages from WD fed LDLRo/CD36o mice secreted similar levels of IL-1α as WD fed LDLRo mice (1084 ± 20.4 pg/mg protein), and consistent with the atherosclerosis data, when fed the HC diet they secreted significantly less IL-1α than HC fed LDLRo mice (1029 ± 192.6 pg/mg protein, p<0.05). Wild type macrophages incubated with plasma (50 ug/ml) from HC fed LDLRo mice secreted 2.1 fold more TNFα (1.657 ± 0.5 vs. 0.745 ± 0.06 pg/mg protein), and 1.5 fold more reactive oxygen species (ROS) (103 ± 13.3 vs. 70.2 ± 5.6 mean fluorescent units/ug protein, p<0.05) than macrophages incubated in WD fed plasma. In comparison with CD36o macrophages, wild type macrophages secreted 1.6 fold more ROS when incubated with plasma from HC fed LDLRo mice (370.4 ± 28 vs. 235.8 ± 20.1 mean fluorescent units/ug protein, p=0.0598). We also measured secretion of IL-1α from wild type and CD36o macrophages treated with HC plasma. Wild type macrophages secreted 1.45 fold more IL-1α compared with CD36o macrophages (170.23 ± 4.5 vs 117.08 ± 2.6 pg/ml, n=4/group, p<0.0001).
Using a cytokine array, we compared responses of wild type and CD36o macrophages to plasma (50 ug/ml, overnight) isolated from WD and HC fed LDLRo mice. Wild type macrophages secreted increased levels of the following cytokines in response to HC compared with WD plasma: granulocyte macrophage colony stimulating factor (2.2 fold), IL-1α (1.5 fold), IL-5 (2.8 fold), IL-6 (38.7 fold), IL-13 (1.9 fold), macrophage colony stimulating factor (1.8 fold), KC (5.1 fold), macrophage inflammatory protein (MIP)-1α (4.6 fold), MIP-1β (17.7 fold), MIP-2 (2.4 fold), RANTES (11 fold), TNF-α (3.5 fold) and triggering receptor expressed on myeloid cells-1 (2 fold). These were CD36 dependent responses based on the observation that macrophages from CD36o mice showed no increase (or a decrease) in cytokine secretion of these cytokines when incubated with HC plasma in comparison with WD plasma.
To determine if these in vitro pro-inflammatory changes also occurred in the physiological setting of the different diets, we analyzed plasma (n = 5/group) from 12 week diet fed mice. In HC fed LDLRo mice, we found increased levels of IL-1β (2.72x; 17.54 ± 2.41 vs 6.49 ± 1.21 pg/ml, p<0.005), IL-2 (1.85x; 10.92 ± 2.01 vs 5.9 ± 2.38 pg/ml), IL-4 (2.36x; 11.04 ± 1.34 vs 4.68 ± 1.37 pg/ml, p<0.05), IL-6 (2.34x; 25.1 ± 8.7 vs 10.72 ± 3.25 pg/ml), and TNFα (2.73x; 18.08 ± 2.5 vs 6.62 ± 4.3 pg/ml) compared with WD fed LDLRo mice; IL-10 levels did not differ (21.83 ± 2.15 vs 26.09 ± 4.2 pg/ml). An increased pro-inflammatory state was further evidenced by significantly increased plasma levels of soluble VCAM-1 in HC fed LDLRo mice compared with WD fed LDLRo mice (594.4 ± 23.1 (n = 10) vs. 477.2 ± 20.8 (n = 9) pg/ml, p<0.005). Increased inflammation may also affect peripheral blood differential counts. Compared with WD fed LDLRo mice, HC fed LDLRo mice had a significantly higher number of neutrophils (27.0 ± 3.7 vs. 12.5 ± 0.4, n = 3/group, p<0.05).
In this report, we exploited the differences between the LDLRo and apoEo models of atherosclerosis to better define conditions of CD36-dependent atherogenesis. The major finding is that increased LDL cholesterol alone does not create significant ligands for CD36-mediated atherosclerosis; inflammation is a key element. These results provide a potential critical link to the observation that increased inflammation accelerates atherosclerosis. Under these conditions, CD36-mediated atherogenesis may contribute significantly.
Our observation that there was no protection against atherosclerotic lesion development in Western diet fed LDLRo mice was consistent with data showing that LDL isolated from LDLRo mice was not as atherogenic as LDL isolated from apoEo mice (24). In order to investigate ligand differences in vivo, we used 2 approaches: reciprocal transfer of macrophages into the peritoneal cavities of hyperlipidemic apoEo and LDLRo mice, and bone marrow transplant of apoEo mice with LDLRo/CD36o and LDLRo stem cells. Both strongly suggested that it was the pro-atherogenic lipoprotein in the apoEo mouse which led to CD36-dependent atherosclerosis, and not differences in apoEo and LDLRo macrophage function. In vitro, incubation of macrophages isolated from LDLRo and LDLRo/CD36o mice with oxLDL and NO2LDL further supported the hypothesis that differences in ligand properties were important to CD36-dependent atherogenesis.
Because others have shown that increased cholesterol in the diet of LDLRo mice increases inflammation, oxidant stress and atherosclerotic lesion burden, we used this approach to determine if this would affect CD36-dependent atherogenesis in the LDLRo (18, 27). Overall, the percent cholesterol in the HDL fraction as a function of total cholesterol did not differ greatly in WD fed mice compared with HC fed mice, except in the case of high cholesterol fed CD36o/LDLRo female mice, where it was lower, ruling out differences in HDL as contributing to the mechanism of the outcome.
WD and HC fed LDLRo mice had similar risk factors (greater weight gain, insulin resistance) that were significantly different from LDLRo/CD36o mice, thus it seems unlikely this explains the different outcomes in terms of lesion. We also used a second diet enriched with cholesterol, that otherwise contained the exact components of the WD, to rule out potential differences in fatty acids that may have confounded our results. We again observed CD36-dependent atherosclerosis.
Morphologically, we observed significant differences in lesions of male mice fed either the Western or high cholesterol diet at the level of the aortic sinus. We noted decreased oil red O staining in both Western diet and high cholesterol diet fed LDLRo/CD36o mice, indicating a probable decrease in macrophage foam cells. In other work, we have found that CD36 plays a role in migration to lesions, and to retention of macrophages in response to oxLDL (28, 29). These observations support the finding of fewer macrophages in lesions of LDLRo/CD36o mice, which has also been observed in apoEo/CD36o mice (13). In high cholesterol diet fed male LDLRo/CD36o mice, we observed increased areas of acellularity/necrosis, which were also observed previously by Moore et al. in lesions from female apoEo/CD36o (13). Manning-Tobin, et al. have suggested that ligands of CD36 play a role in the ER stress-pro apoptotic response (30). One would then hypothesize fewer areas of necrosis in mice lacking CD36. An alternative hypothesis is that absence of CD36 promotes the pro-apoptotic role of ligands of scavenger receptor A I/II, and combined with absence of CD36-mediated clearance of apoptotic cells, leads to increased areas of necrosis (31–33). The reasons for the apparent gender specific differences in lesion morphology are unknown but may reflect different stages of lesion development/remodeling.
In vitro studies demonstrated that LDL isolated from HC fed mice led to greater jnk phosphorylation, which is CD36-dependent, than LDL isolated from WD fed LDLRo mice. These results support those of Zhao et al. (24), in that they show that LDL from WD fed LDLRo mice is not a functional ligand for CD36. We demonstrated that CD36-dependent jnk phosphorylation was critical to uptake of oxidatively modified LDL and foam cell formation (10), and more recently, that this pathway was activated by CD36 ligands in platelets and led to a hyperreactive phenotype (34, 35). Inhibition of jnk has been shown to result in reduced atherosclerosis in mice (36). Thus inefficient activation of this CD36-mediated pro-atherogenic pathway provides a potential mechanism for the absence of CD36-dependent atherogenesis in WD (and perhaps NC) fed hyperlipidemic LDLRo mice.
In response to oxidatively modified LDL, which is physiologically relevant since it has been shown to be present in atherosclerotic plaque of mice and humans (8, 9), we noted increased secretion of the pro-inflammatory cytokine IL-1α, from macrophages isolated from HC fed mice compared with those isolated from WD fed mice. These data suggest that exposure to increased cholesterol increases the inflammatory nature of macrophages. Others have noted an increase in the secretion of IL-1β from human macrophages exposed to oxLDL that was CD36 dependent (37). Plasma/LDL from high cholesterol fed LDLRo mice elicited greater secretion of TNFα and reactive oxygen species compared with plasma/LDL from WD fed LDLRo mice. Plasma from HC fed LDLRo mice had significantly higher levels of IL-1β, IL-2, IL-4, IL-6, and soluble VCAM-1, indicators of increased inflammation, compared to plasmas from WD fed LDLRo mice. Increased levels of soluble VCAM-1 may result from increased activity of metalloproteinases, elastase, cathepsins and phospholipases, which are also increased in atherosclerosis and inflammatory settings (38).
Others have found that increased dietary cholesterol in this model leads to increased numbers of adipose tissue macrophages and increased atherosclerosis with chronic systemic inflammation and insulin resistance (39). We did not specifically measure adipose macrophage number in our study, but our results showing increased inflammation, insulin resistance and atherosclerosis confirm the effect of cholesterol addition and moreover suggest that the pro-atherosclerotic mechanism is at least partially CD36-dependent
An increase in inflammatory milieu is associated with increased oxidative stress (40), and this may lead to changes in lipoproteins that render them more pro-atherogenic, and more likely to be a ligand for CD36. In other work, we showed that oxidation of LDL led to the creation of specific truncated sn-2 position fatty acids in phospholipids that are high affinity ligands for CD36 (oxPCCD36) (8, 9). Recognition of these altered fatty acid chains by CD36 was shown to be a result of a change in conformation, such that they no longer remain in the hydrophobic core of the lipoprotein (41). We have also shown that these ligands may contribute to the pro-thrombotic phenotype associated with hyperlipidemia and oxidant-stress states by interacting with platelet CD36 (34). The present work is consistent with the hypothesis that inflammatory cell modification of lipoproteins creates ligands for receptors such as CD36 and is a significant pro-atherogenic pathway. Our results are presently correlative and do not preclude other pathways, including aggregation of lipoproteins, entrapment in the vessel wall, and macropinocytosis (42, 43), but it does suggest a mechanism for the observation that increased inflammation accelerates atherosclerosis and leads to increased atherosclerotic lesion burden.
Relevance to human disease is, of course, the underlying reason for studying murine models. Human atherosclerosis is recognized as a chronic pro-inflammatory disease, and targeting genes that relate to promotion of the inflammatory state has proven to be an effective way to impact lesion formation. In fact, some of the protective effects of statins and agonists of PPARγ and LXRα are now recognized as attributable to anti-inflammatory properties (44–46). Risk factors related to inflammation, including insulin resistance/diabetes, obesity, smoking, gingivitis, and auto-immune diseases such as lupus and Crohn’s disease, all increase potential for accelerated atherosclerosis. Our study suggests that the inflammatory milieu may trigger a scavenger-receptor mediated component to atherogenesis that acts in concert with hyperlipidemia. Our study also may explain some discrepancies in atherosclerosis studies in the literature, and underscores the differences between the two most commonly used murine atherosclerosis models. Further research is warranted to determine the implications of CD36-mediated atherogenesis in other pro-inflammatory settings.
Sources of Funding
This research was supported by NIH HL 70083 (M. Febbraio). David Kennedy is supported by the Lerner Research Institute's Morgenthaler Fellowship and American Heart Association Postdoctoral Fellowship 0825685D.