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W Jessup

Publications and source records attributed to W Jessup.

At least 19 recordsLinked to original sources
PubMed2001

Enhancement of macrophage survival and DNA synthesis by oxidized-low-density-lipoprotein (LDL)-derived lipids and by aggregates of lightly oxidized LDL.

Human atherosclerotic plaque contains a partially characterized range of normal and oxidized lipids formed mainly from free and esterified cholesterol and phospholipids, some of which can be located in macrophage-derived "foam" cells. Oxidation of low-density lipoprotein (LDL) is often considered as an important event leading to subsequent foam-cell development, which may also include enhanced cell survival and/or proliferation. The active component(s) in oxidized LDL (ox.LDL) causing macrophage proliferation is debated. We report here that the lipid component of ox.LDL can promote macrophage survival and DNA synthesis, the latter response showing a synergistic effect in the presence of low concentrations of macrophage colony-stimulating factor. 7-Ketocholesterol showed some stimulation of macrophage DNA synthesis whereas hypochlorite-oxidized (i.e. apolipoprotein B-oxidized) LDL did not. Plaque-derived lipids could enhance macrophage survival. It has not been proven that LDL in lesions is oxidized sufficiently to be the dominant source of sterols in vivo or to be able to induce macrophage growth in vitro or in vivo; it has been suggested that aggregation of modified LDL in vivo is an important step in the deposition of intracellular lipid. We found that aggregation of lightly oxidized LDL potentiated dramatically its ability to stimulate macrophage DNA synthesis, indicating that extensive oxidation of LDL is not required for this response in vitro and perhaps in vivo.

Animals↗
PubMed2001

Comparison of macrophage responses to oxidized low-density lipoprotein and macrophage colony-stimulating factor (M-CSF or CSF-1).

Modification of low-density lipoprotein (LDL), for example by oxidation, could be involved in foam cell formation and proliferation observed in atherosclerotic lesions. Macrophage colony-stimulating factor (CSF-1 or M-CSF) has been implicated in foam cell development. It has been reported previously that oxidized LDL (ox.LDL) and CSF-1 synergistically stimulate DNA synthesis in murine bone-marrow-derived macrophages (BMM). The critical signal-transduction cascades responsible for the proliferative response to ox.LDL, as well as their relationship to those mediating CSF-1 action, are unknown. We report here that ox.LDL stimulated extracellular signal-regulated protein kinase (ERK)-1, ERK-2 and phosphoinositide 3-kinase activities in BMM but to a weaker extent than optimal CSF-1 concentrations at the time points examined. Inhibitor studies suggested at least a partial role for these kinases, as well as p70 S6-kinase, in ox.LDL-induced macrophage survival and DNA synthesis. For the DNA synthesis response to CSF-1, the degree of inhibition by PD98059, wortmannin and rapamycin was significant at low CSF-1 concentrations but was reduced as the CSF-1 dose increased. Using BMM from CSF-1-deficient mice (op/op) and a neutralizing antibody approach, we found no evidence for an essential role for endogenous CSF-1 in ox.LDL-mediated survival or DNA synthesis; likewise, with the same approaches, no evidence was obtained for an essential role for endogenous granulocyte/macrophage-CSF in ox.LDL-mediated macrophage survival and, in contrast with the literature, ox.LDL-induced macrophage DNA synthesis.

Androstadienes↗
PubMed2000

Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture.

27-Hydroxycholesterol (27OH) is the major oxysterol in human atherosclerotic lesions, followed by 7-ketocholesterol (7K). Whereas 7K probably originates nonenzymically, 27OH arises by the action of sterol 27-hydroxylase, a cytochrome P450 enzyme expressed at particularly high levels in the macrophage and proposed to represent an important pathway by which macrophages eliminate excess cholesterol. We hypothesized and here show that 27-hydroxylated 7-ketocholesterol (270H-7K) is present in human lesions, probably generated by the action of sterol 27-hydroxylase on 7K. Moreover, [(3)H]27OH-7K was produced by human monocyte-derived macrophages (HMDMs) supplied with [(3)H]7K but not in HMDMs from a patient with cerebrotendinous xanthomatosis (CTX) shown to have a splice-junction mutation of sterol 27-hydroxylase. Whereas [(3)H]27OH-7K was predominantly secreted into the medium, [(3)H]-27OH formed from [(3)H]-cholesterol was mostly cell-associated. The majority of supplied [(3)H]7K was metabolized beyond 27OH-7K to aqueous-soluble products (apparently bile acids derived from the sterol 27-hydroxylase pathway). Metabolism to aqueous-soluble products was ablated by a sterol 27-hydroxylase inhibitor and absent in CTX cells. Sterol 27-hydroxylase therefore appears to represent an important pathway by which macrophages eliminate not only cholesterol but also oxysterols such as 7K. The fact that 7K (and cholesterol) still accumulates in lesions and foam cells indicates that this pathway may be perturbed in atherosclerosis and affords a new opportunity for the development of therapeutic strategies to regress atherosclerotic lesions.

Adult↗
PubMed2000

Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis.

BACKGROUND: Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. METHODS AND RESULTS: Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/microgram total RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (P=0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%, and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (P>0.2 versus controls). CONCLUSIONS: Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.

Adult↗
PubMed2000

Macrophages can decrease the level of cholesteryl ester hydroperoxides in low density lipoprotein.

Murine and human macrophages rapidly decreased the level of cholesteryl ester hydroperoxides in low density lipoprotein (LDL) when cultured in media non-permissive for LDL oxidation. This process was proportional to cell number but could not be attributed to the net lipoprotein uptake. Macrophage-mediated loss of lipid hydroperoxides in LDL appears to be metal ion-independent. Degradation of cholesteryl linoleate hydroperoxides was accompanied by accumulation of the corresponding hydroxide as the major product and cholesteryl keto-octadecadienoate as a minor product, although taken together these products could not completely account for the hydroperoxide consumption. Cell-conditioned medium possessed a similar capacity to remove lipid hydroperoxides as seen with cellular monolayers, suggesting that the activity is not an integral component of the cell but is secreted from it. The activity of cell-conditioned medium to lower the level of LDL lipid hydroperoxides is associated with its high molecular weight fraction and is modulated by the availability of free thiol groups. Cell-mediated loss of LDL cholesteryl ester hydroperoxides is facilitated by the presence of alpha-tocopherol in the lipoprotein. Together with our earlier reports on the ability of macrophages to remove peroxides rapidly from oxidized amino acids, peptides, and proteins as well as to clear selectively cholesterol 7-beta-hydroperoxide, results presented in this paper provide evidence of a potential protective activity of the cell against further LDL oxidation by removing reactive peroxide groups in the lipoprotein.

Animals↗
PubMed2000

HMG CoA reductase inhibition reduces sarcolemmal Na(+)-K(+) pump density.

OBJECTIVES: HMG CoA reductase inhibitors reduce cellular availability of mevalonate, a precursor in cholesterol synthesis. Since the cholesterol content of cell membranes is an important determinant of Na(+)-K(+) pump function we speculated that treatment with HMG CoA reductase inhibitors affects Na(+)-K(+) pump activity. METHODS: We treated rabbits and rats for 2 weeks with the HMG CoA reductase inhibitor lovastatin and measured Na(+)-K(+) pump current (I(p)) in isolated rabbit cardiac myocytes using the whole cell patch-clamp technique, K-dependent p-nitrophenyl phosphatase (p-NPPase) activity in crude myocardial and skeletal muscle homogenates, and vanadate-facilitated 3H-ouabain binding in intact skeletal muscle samples from rats. RESULTS: Treatment with lovastatin caused statistically significant reductions in I(p), myocardial and skeletal muscle K-dependent p-NPPase activity and 3H-ouabain binding in the myocardium and skeletal muscle. The lovastatin-induced decrease in I(p) was eliminated by parenteral co-administration of mevalonate. However, this was not related to cardiac cholesterol content. CONCLUSIONS: Treatment with lovastatin reduces Na(+)-K(+) pump activity and abundance in rabbit and rat sarcolemma.

4-Nitrophenylphosphatase↗
PubMed2000

Metabolism of oxidized LDL by macrophages.

Oxidation products of lipids and proteins are found in atherosclerotic plaque and in macrophage foam cells. Macrophages avidly endocytose in-vitro oxidized LDL and accumulate sterols. What is the evidence that such a process is involved in in-vivo foam cell formation? The present review surveys current knowledge on the metabolism of oxidized LDL by macrophages, and the types, amounts and location of oxidation products that accumulate in these cells. Comparable studies of lesion lipoproteins and foam cells indicate that limited extracellular lipoprotein oxidation, perhaps followed by more extensive intracellular oxidation subsequent to uptake by macrophages, is a more likely scenario in vivo.

Animals↗
PubMed2000

Apolipoprotein A-I, cyclodextrins and liposomes as potential drugs for the reversal of atherosclerosis. A review.

Several studies have revealed that high-density lipoprotein (HDL) is the most reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile evaluating the potential of this protein to reduce the lipid burden of lesions observed in the clinic. Indeed, apoA-I is used extensively in cell culture to induce cholesterol efflux. However, while there is a large body of data emanating from in-vitro and cell-culture studies with apoA-I, little animal data and scant clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exists. Importantly, the effects of oxysterols, such as 7-ketocholesterol (7KC), on cholesterol and other lipid efflux by apoA-I needs to be investigated in any attempt to utilise apoA-I as an agent to stimulate efflux of lipids. Lessons may be learnt from studies with other lipid acceptors such as cyclodextrins and phospholipid vesicles (PLVs, liposomes), by combination with other effluxing agents, by remodelling the protein structure of the apolipoprotein, or by altering the composition of the lipoprotein intended for administration in-vivo. Akin to any other drug, the usage of this apolipoprotein in a therapeutic context has to follow the traditional sequence of events, namely an evaluation of the biodistribution, safety and dose-response of the protein in animal trials in advance of clinical trials. Mass production of the apolipoprotein is now a simple process due to the advent of recombinant DNA technology. This review also considers the potential of cyclodextrins and PLVs for use in inducing reverse cholesterol transport in-vivo. Finally, the potential of cyclodextrins as delivery agents for nucleic acid-based constructs such as oligonucleotides and plasmids is discussed.

Apolipoprotein A-I↗
PubMed2000

Regulation of apolipoprotein E production in macrophages (review).

Apolipoprotein E (apo E), a 34 kDa component of lipoproteins produced by the liver and in circulating macrophages, plays a critical role in the reverse transport of cholesterol to the liver via the circulation. Cholesterol-rich macrophages (macrophage foam cells) are a major cell type in human atherosclerotic lesions. Apo E deficiency in mice leads to the formation of atherosclerotic lesions. Conversely, macrophage-specific expression of apo E in these deficient mice can reduce the extent of atherosclerosis. These observations, together with the anti-inflammatory and anti-proliferative properties of Apo E, demonstrate an atheroprotective role for the apolipoprotein. Agents that regulate macrophage metabolism are also able to modulate apo E expression. Sterol loading, for example, enhances apo E synthesis and secretion. Additionally, exposure of macrophage foam cells to cholesterol acceptors such as apo A-1, the protein component of high density lipoprotein, further enhance apo E secretion. Cytokines can have a negative regulatory effect on apo E production in macrophages. Apo E expression is controlled at the transcriptional, post-transcriptional and post-translational level. Here, we review the cellular and molecular mechanisms modulating apo E synthesis and secretion in macrophages.

Animals↗
PubMed2000

Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells. Accumulation of oxidized esters in lysosomes.

Cholesterol- and cholesteryl ester-rich macrophage foam cells, characteristic of atherosclerotic lesions, are often generated in vitro using oxidized low density lipoprotein (OxLDL). However, relatively little is known of the nature and extent of sterol deposition in these cells or of its relationship to the foam cells formed in atherosclerotic lesions. The purpose of this study was to examine the content and cellular processing of sterols in OxLDL-loaded macrophages, and to compare this with macrophages loaded with acetylated LDL (AcLDL; cholesteryl ester-loaded cells containing no oxidized lipids) or 7-ketocholesterol-enriched acetylated LDL (7KCAcLDL; cholesteryl ester-loaded cells selectively supplemented with 7-ketocholesterol (7KC), the major oxysterol present in OxLDL). Both cholesterol and 7KC and their esters were measured in macrophages after uptake of these modified lipoproteins. Oxysterols comprised up to 50% of total sterol content of OxLDL-loaded cells. Unesterified 7KC and cholesterol partitioned into cell membranes, with no evidence of retention of either free sterol within lysosomes. The cells also contained cytosolic, ACAT-derived, cholesteryl and 7-ketocholesteryl esters. The proportion of free cholesterol and 7KC esterified by ACAT was 10-fold less in OxLDL-loaded cells than in AcLDL or 7KCAcLDL-loaded cells. This poor esterification rate in OxLDL-loaded cells was partly caused by fatty acid limitation. OxLDL-loaded macrophages also contained large (approximately 40-50% total cell sterol content) pools of oxidized esters, containing cholesterol or 7KC esterified to oxidized fatty acids. These were insensitive to ACAT inhibition, very stable and located in lysosomes, indicating resistance to lysosomal esterases. Macrophages loaded with OxLDL do not accumulate free sterols in their lysosomal compartment, but do accumulate lysosomal deposits of OxLDL-derived cholesterol and 7-ketocholesterol esterified to oxidized fatty acids. The presence of similar deposits in lesion foam cells would represent a pool of sterols that is particularly resistant to removal.

Animals↗
PubMed1999

Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: a sex-specific effect.

BACKGROUND: Males have an earlier onset and greater prevalence of clinical atherosclerosis than age-matched females, which is consistent with an atheroprotective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis. METHODS AND RESULTS: Monocytes from healthy female and male donors were obtained from white cell concentrates and allowed to differentiate into macrophages over 10 days. These human monocyte-derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol) or estrogen or progesterone treatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17beta-Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) concentrations produced a significant reduction in macrophage CE content (88+/-3%, 88+/-2%, and 85+/-4%, respectively; P<0.02 compared with control). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (74+/-9%, 56+/-10%, and 65+/-8%, respectively; P<0.002 compared with control). This effect could be abrogated by coincubation with the progesterone receptor antagonist RU486. Neither estrogen nor progesterone produced a reduction in lipid loading in male-donor-derived MDMs. Detailed lipid trafficking studies demonstrated that both estrogen and progesterone altered macrophage uptake and/or processing of modified LDL. CONCLUSIONS: Physiological levels of estrogen and progesterone are associated with a female-sex-specific reduction in human macrophage lipid loading, which is consistent with an atheroprotective effect.

Acetylation↗
PubMed1999

Apolipoprotein A-I stimulates secretion of apolipoprotein E by foam cell macrophages.

Apolipoprotein A-I (apoA-I) overexpression inhibits atherogenesis in mice, and apolipoprotein E (apoE) secreted by foam cell macrophages may exert antiatherogenic effects within the arterial wall. We hypothesized that interaction between apoA-I and apoE contributed to the antiatherogenic properties of apoA-I, and therefore investigated whether apoA-I stimulated secretion of apoE by foam cell macrophages. Cholesterol enrichment of primary murine and human macrophages increased spontaneous apoE secretion 2-fold, as quantified by Western blot and chemiluminescence detection. Human apoA-I caused a further marked increase of apoE secretion from both murine (3.8-fold, p < 0.01) and human (3.2-fold, p = 0.01) foam cells in a time- and concentration- dependent manner, and this increase was confirmed by immunoprecipitation of [(35)S]methionine-labeled macrophage apoE. The protein synthesis inhibitor cycloheximide, but not the transcription inhibitor actinomycin D, markedly inhibited apoE secretion to apoA-I (73.1 +/- 9.8% inhibition at 4 h) and completely suppressed apoE secretion beyond 4 h. Pretreatment of macrophages with Pronase inhibited initial apoA-I-mediated apoE secretion by 70.5 +/- 6.5% at 2 h, but by 8 h apoA-I-induced apoE secretion was the same in Pronase-pretreated and non-pretreated cells. Non-apolipoprotein-mediated cholesterol efflux induced by trimethyl-beta cyclodextrin did not enhance apoE secretion, whereas phospholipid vesicles inducing the same degree of cholesterol efflux substantially enhanced apoE secretion, and apoA-I and phospholipid vesicles in combination demonstrated additive induction of apoE secretion. We conclude that apoA-I concurrently stimulates apoE secretion and cholesterol efflux from foam cell macrophages and that lipoprotein-derived apoA-I may enhance local secretion and accumulation of apoE in atherosclerotic lesions.

Animals↗
PubMed1999

Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1.

BACKGROUND: Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell-surface expression of adhesion molecules. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 micromol/L); HF alone; or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37 degrees C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116+/-6% and 128+/-3% for DHT 40 and 400 nmol/L respectively; P<0.001). HF blocked this increase (P>/=0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125+/-5% versus 100+/-4% in controls; P=0.002), an effect also antagonized by HF (P>/=0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti-VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-alpha. CONCLUSIONS: Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell-surface expression of VCAM-1.

Antibodies, Monoclonal↗
PubMed1999

The macrophage in atherosclerosis: modulation of cell function by sterols.

Lipid-laden macrophage foam cells are an early and persistent component of atherosclerotic lesions. As such they are likely to play a key role in disease progression, both as scavengers of lipid and as inflammatory mediators. The sterol content of macrophage foam cells is largely native cholesterol together with a small but significant proportion of oxidized cholesterol (oxysterols). Few in vitro investigations of the influence of sterol accumulation on macrophage function have used cells that contain physiologically or even pathologically representative amounts of cholesterol or, more particularly, oxysterols. However, recent studies, using macrophages with a sterol content much closer to that of authentic foam cells, show that the presence of oxysterols causes an impairment in macrophage cholesterol export, suggesting a key role for oxysterols in the maintenance of the foam cell phenotype. The implications of physiologically relevant levels of oxysterols on a wider range of macrophage function remain to be investigated.

Animals↗
PubMed1999

Oxysterols and atherosclerosis.

Oxysterols are present in human atherosclerotic plaque and are suggested to play an active role in plaque development. Moreover, the oxysterol:cholesterol ratio in plaque is much higher than in normal tissues or plasma. Oxysterols in plaque are derived both non-enzymically, either from the diet and/or from in vivo oxidation, or (e.g. 27-hydroxycholesterol) are formed enzymically during cholesterol catabolism. While undergoing many of the same reactions as cholesterol, such as being esterified by cells and in plasma, certain oxysterols in some animal and in vitro models exhibit far more potent effects than cholesterol per se. In vitro, oxysterols perturb several aspects of cellular cholesterol homeostasis (including cholesterol biosynthesis, esterification, and efflux), impair vascular reactivity and are cytotoxic and/or induce apoptosis. Injection of relatively large doses of oxysterols into animals causes acute angiotoxicity whereas oxysterol-feeding experiments have yielded contrary results as far as their atherogenicity is concerned. There is no direct evidence yet in humans that oxysterols contribute to atherogenesis. However, oxysterol levels are elevated in human low-density lipoprotein (LDL) subfractions that are considered potentially atherogenic and two recent studies have indicated that raised plasma levels of a specific oxysterol (7beta-hydroxycholesterol) may be associated with an increased risk of atherosclerosis. At the present time there are a number of significant and quite widespread problems with current literature which preclude more than a tentative suggestion that oxysterols have a causal role in atherogenesis. Further studies are necessary to definitively determine the role of oxysterols in atherosclerosis, and considering the wide-ranging tissue levels reported in the literature, special emphasis is needed on their accurate analysis, especially in view of the susceptibility of the parent cholesterol to artifactual oxidation.

Animals↗
PubMed1999

Oxidized LDL can induce macrophage survival, DNA synthesis, and enhanced proliferative response to CSF-1 and GM-CSF.

Modification of low density lipoprotein (LDL), eg, by oxidation, has been proposed as being important for the formation of foam cells and therefore for the development of atherosclerotic plaques. There are a number of reports showing that macrophage-derived foam cells can proliferate in both human and animal lesions, particularly in the early phase of the disease and possibly involving macrophage-colony stimulating factor (M-CSF, or CSF-1). We studied the in vitro effects of oxidized LDL (ox-LDL) on murine bone marrow-derived macrophages (BMMs), a cell population with a high proliferative capacity in vitro in response to CSF-1 and a dependence for survival on the presence of this growth factor. We report here that treatment of BMMs with low doses of ox-LDL, but not with native LDL, led to cell survival, DNA synthesis, and an enhanced response to the proliferative actions of CSF-1 and granulocyte macrophage-CSF (GM-CSF); the effects were dependent on the degree of LDL oxidation. For CSF-1, a synergistic effect was noticeable at suboptimal doses. The effect of ox-LDL occurred even in the absence of endogenous CSF-1 or GM-CSF. Our findings suggest that ox-LDL, and possibly other modified forms of LDL, could maintain macrophage (and foam cell) survival and therefore lengthen their tenure in a plaque; the modified LDL could also cause local macrophage proliferation or "prime" them so that they could proliferate better in response to CSF-1 (and GM-CSF) concentrations that may be present in the atheroma.

Animals↗