Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We and others previously showed that immunization of rabbits with different forms of oxidized low density lipoprotein (LDL) significantly reduced atherogenesis. We now investigated the effect of continued immunization on atherosclerosis in LDL receptor-deficient (LDLR-/-) mice to determine whether a similar reduction of atherosclerosis occurred in murine models and whether this was due to humoral immune responses, ie, formation of high titers of antibodies to oxidation-specific epitopes. Three groups of LDLR-/- mice were repeatedly immunized with homologous malondialdehyde-modified LDL (MDA-LDL), native LDL, or phosphate-buffered saline (PBS) for 7 weeks. Extensive hypercholesterolemia and accelerated atherogenesis were then induced by feeding a cholesterol-rich diet for 17 weeks, during which immunizations were continued. Binding of immunoglobulin (Ig) M and IgG antibodies, as well as IgG1 and IgG2a isotypes, to several epitopes of oxidized LDL were followed throughout the study. After 24 weeks of intervention, atherosclerosis in the aortic origin was significantly reduced by 46.3% and 36.9% in mice immunized with MDA-LDL and native LDL, respectively, compared with PBS (133 558 and 157 141 versus 248 867 microm2 per section, respectively). However, the humoral immune response to oxidative neoepitopes in the MDA-LDL group was very different from that of the LDL or PBS group. IgG antibody binding to MDA-LDL and other epitopes of oxidized LDL, such as oxidized phospholipid (cardiolipin), oxidized cholesterol, or oxidized cholesteryl linoleate, but not native LDL, increased markedly in mice immunized with MDA-LDL, but not in mice immunized with native LDL or PBS. In the MDA-LDL group, both T helper cell (Th)2-dependent IgG1 antibody and Th1-dependent IgG2a antibody binding to oxidative neoepitopes increased significantly over time. The fact that mice immunized with both MDA-LDL and native LDL had a significant reduction in atherosclerosis, whereas only the MDA-LDL group developed very high titers of antibodies to oxidation-specific epitopes, suggests that the antiatherogenic effect of immunization is not primarily dependent on very high titers of antibodies to oxidation-specific epitopes but is more likely to result from the activation of cellular immune responses.
 ...
PMID:Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. 984 92

Low density lipoprotein (LDL) receptor-deficient (LDLR-/-) mice consuming a high fat diet were used to assess the effect of endogenous and exogenous estradiol (E2) on atherosclerosis. Sexually mature female mice were ovariectomized (OVX) and implanted with subcutaneous, slow-release pellets designed to release 6 microg/day of exogenous 17beta-estradiol (17beta-E2 ), 17alpha-estradiol (17alpha-E2 ), or placebo (E2- deficient). Sham-operated control female (endogenous E2 ) and male mice were studied as controls. Aortic atherosclerotic lesion area was reduced by physiologic amounts of both endogenous and exogenous E2 compared to E2-deficient female mice. Although plasma cholesterol levels were reduced by exogenous E2 despite the absence of the LDL receptor, endogenous E2 was not associated with any cholesterol changes. In contrast, only 17alpha-E2 was associated with decreased fasting triglyceride. In subgroup analyses matched for time-averaged plasma total cholesterol, aortic lesion area was reduced by the presence of estradiol (E2 ). E2 protected LDLR-/- female mice from atherosclerosis and this protection was independent of changes in plasma cholesterol levels.
 ...
PMID:Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice. 1022 58

The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR-/-) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR-/- mice; and (3) hypercholesterolemic LDLR-/- mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR-/- mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; n=16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (n=18), or regular chow (n=7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849+/-268 versus 964+/-234 mg/dL) and much higher than in the chow-fed group (249+/-21 mg/dL). Final body weights in the Western diet group were higher (39+/-6.2 g) than in the fructose- (27.8+/-2.7 g) or chow-fed (26.7+/-3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187+/-16 versus 159+/-12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8+/-2.9% versus 7.8+/-2. 5% of aortic surface; P<0.01). These results suggest that (1) fructose-enriched diets do not induce IR in LDLR-/- mice; (2) the Western diets commonly used in LDLR-/- mice may not only induce atherosclerosis, but also IR, potentially complicating the interpretation of results; and (3) IR and hyperinsulinemia do not enhance atherosclerosis in LDLR-/- mice, at least under conditions of very high plasma cholesterol levels. The fact that various levels of hypercholesterolemia can be induced in LDLR-/- mice by fat-enriched diets and that such diets induce IR and hyperinsulinemia suggest that LDLR-/- mice may be used as models to elucidate the effect of IR on atherosclerosis, eg, by feeding them Western diets with or without insulin-sensitizing agents.
 ...
PMID:Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. 1032 73

Past studies of atherosclerosis in mice have used chow-based diets supplemented with cholesterol, lipid, and sodium cholate to overcome species resistance to lesion formation. Similar diets have been routinely used in studies with LDL receptor-deficient (LDLR(-/-)) mice. The nonphysiological nature and potential toxicity of cholate-containing diets have led to speculation that atherogenesis in these mice may not accurately reflect the human disease process. We have designed a semipurified AIN-76A-based diet that can be fed in powdered, pelleted, or liquid form and manipulated for the precise evaluation of diet-genetic interactions in murine atherosclerosis. LDLR(-/-) mice were randomly assigned among 4 diets (n=6/diet) as follows: 1, control, 10% kcal lipid; 2, high fat (40% kcal), moderate cholesterol (0.5% by weight); 3, high fat, high cholesterol (1.25% by weight); and 4, high fat, high cholesterol, and 0.5% (wt/wt) sodium cholate. Fasting serum cholesterol was increased in all cholesterol-supplemented mice compared with controls after 6 or 12 weeks of feeding (P<0.01). The total area of oil red O-stained atherosclerotic lesions was determined from digitally scanned photographs. In contrast to the control group, all mice in cholesterol-supplemented dietary groups 2 to 4 had lesions involving 7.01% to 12.79% area of the thoracic and abdominal aorta at 12 weeks (P<0.002, for each group versus control). The distribution pattern of atherosclerotic lesions was highly reproducible and comparable. The histological features of lesions in mice fed cholate-free or cholate-containing diets were similar. This study shows that sodium cholate is not necessary for the formation of atherosclerosis in LDLR(-/-) mice and that precisely defined semipurified diets are a valuable tool for the examination of diet-gene interactions.
 ...
PMID:Hyperlipidemia and atherosclerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate. 1044 74

The very low density lipoprotein receptor (VLDLR) is a multifunctional apolipoprotein (apo) E receptor that shares a common structural feature as well as some ligand specificity to apo E with members of the low density lipoprotein receptor gene family. We have isolated and characterized the mouse VLDLR gene. The mouse VLDLR gene contains 19 exons spanning approximately 50 kb. The exon-intron organization of the gene is completely conserved between mouse and human. Since the 5'-flanking region of the mouse VLDLR gene contains two copies of a sterol regulatory element-1 like sequence (SRE-1), we next studied regulation of the VLDLR mRNA expression in heart, skeletal muscle and adipose tissue in C57BL/6, LDLR-/-, apo E-/- and LDLR-/-apo E-/- mice fed normal chow or atherogenic diet. The VLDLR mRNA expression was down-regulated 3-fold by feeding atherogenic diet in heart and skeletal muscle only in LDLR-/- mice. In contrast, VLDLR mRNA expression was up-regulated by atherogenic diet in adipose tissue in all animal models except double knockout mice. These results suggest that SRE-1 may be functional and VLDLR plays a role in cholesterol homeostasis in heart and skeletal muscle when LDLR is absent and that apo E is required for this modulation. Developmental regulation of the VLDLR mRNA expression was also tissue-specific. VLDLR mRNA expression in heart displayed significant up and down regulation during development. Maximal level was detected on post-natal day 3. However, the VLDLR mRNA levels in skeletal muscle remained relatively constant except a slight dip on post-natal day 7. In kidney and brain, VLDLR mRNA also peaked on post-natal day 3 but remained relatively constant thereafter. In liver, VLDLR mRNA expression was very low; it was barely detectable at day 19 of gestation and was decreased further thereafter. In adipose tissue, the VLDLR mRNA level showed an increase on post-natal day 13, went down again during weaning and then continued to increase afterwards. This developmental pattern as well as dietary regulation in adipose tissue supports the notion that VLDLR plays a role in lipid accumulation in this tissue. Although the primary role of VLDLR in heart, muscle and adipose tissue is likely in lipid metabolism, developmental pattern of this receptor in other tissues suggests that VLDLR has functions that are unrelated to lipid metabolism.
Atherosclerosis 1999 Aug
PMID:Mouse very low-density lipoprotein receptor (VLDLR): gene structure, tissue-specific expression and dietary and developmental regulation. 1048 49

Functions of mononuclear leukocytes and endothelial cell leukocyte adhesion molecules in the formation of early atherosclerotic lesions is discussed. The main transgenic mouse models developed to study cholesterol metabolism and atherosclerotic lesion formation, including apolipoprotein E knockout and low density lipoprotein receptor knockout (LDLR-/-) mice, are reviewed. Differences in their dependence on dietary cholesterol supplementation is emphasized and a new semi-purified, cholate-free mouse diet for LDLR-/- mice is described. This diet is highly reproducible, versatile (pellet, powder or liquid formulations), inexpensive and promotes hypercholesterolemia and atherosclerotic lesion development despite absence of sodium cholate. We describe the expression patterns of leukocyte adhesion molecules in rabbit and mouse models of atherosclerosis and compare them to humans. Finally, ongoing studies are summarized which utilize transgenic mice to assess the roles of individual adhesion molecules in atherosclerotic lesion formation.
 ...
PMID:Leukocyte adhesion molecules in atherogenesis. 1051 Dec 93

To determine whether labeled antibodies against oxidized LDL (OxLDL) offer advantages for quantifying atherosclerosis, we compared in vivo aortic uptake of (125)I-labeled MDA2, a monoclonal antibody against malondialdehyde-lysine epitopes), atherosclerotic surface area, and aortic weight in Watanabe heritable hyperlipidemic and New Zealand White rabbits and in low density lipoprotein receptor-deficient (LDLR(-/-)) and apolipoprotein E-deficient (apoE(-/-)) mice. Absolute and specific uptakes of (125)I-MDA2 were significantly greater in plaque than in normal aortas. Uptake of (125)I-MDA2 significantly correlated with aortic weight and percent atherosclerotic surface area in rabbits and mice. To assess whether (125)I-MDA2 uptake reflects changes in lesion content of OxLDL, in a separate study, extensive atherosclerosis was induced in 4 groups of LDLR(-/-) mice by feeding them a high fat/cholesterol diet for 6 months. A baseline group was euthanized at this time. The remaining groups were fed "regression" diets (chow or chow+1% vitamin E+0.05% vitamin C) or the high fat/cholesterol diet for 6 more months. When atherosclerosis was measured as percent surface area or aortic weight, there was strong progression in the high fat/cholesterol group, moderate progression in the chow group, and no progression in the chow+vitamin E+vitamin C group compared with the baseline group. The (125)I-MDA2 method also yielded a significant increase in atherosclerosis in the high fat/cholesterol group but significant decreases in the chow and chow+vitamin E+vitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chow+vitamin E+vitamin C groups. Thus, the uptake of (125)I-MDA2 correlates well with traditional measures of atherosclerosis but also reflects reduced plaque OxLDL content after hypocholesterolemic intervention.
 ...
PMID:In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression. 1071 92

Impaired fibrinolysis has been linked to atherosclerosis in a number of experimental and clinical studies. Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of plasminogen activation and has been proposed to promote atherosclerosis by facilitating fibrin deposition within developing lesions. We examined the contribution of PAI-1 to disease progression in 2 established mouse models of atherosclerosis. Mice lacking apolipoprotein E (apoE-/-) and mice lacking the low density lipoprotein receptor (LDLR-/-) were crossbred with transgenic mice overexpressing PAI-1 (resulting in PAI-1 Tg(+)/apoE-/- and PAI-1 Tg(+)/LDLR-/-, respectively) or were crossbred with mice completely deficient in PAI-1 gene expression (resulting in PAI-1-/-/apoE-/- and PAI-1-/-/LDLR-/-, respectively). All animals were placed on a western diet (21% fat and 0.15% cholesterol) at 4 weeks of age and analyzed for the extent of atherosclerosis after an additional 6, 15, or 30 weeks. Intimal and medial areas were determined by computer-assisted morphometric analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions were also characterized by histochemical analyses with the use of markers for smooth muscle cells, macrophages, and fibrin deposition. Typical atherosclerotic lesions were observed in all experimental animals, with greater severity at the later time points and generally more extensive lesions in apoE-/- than in comparable LDLR-/- mice. No significant differences in lesion size or histological appearance were observed among PAI-1-/-, PAI-1 Tg(+), or PAI-1 wild-type mice at any of the time points on either the apoE-/- or LDLR-/- genetic background. We conclude that genetic modification of PAI-1 expression does not significantly alter the progression of atherosclerosis in either of these well-established mouse models. These results suggest that fibrinolytic balance (as well as the potential contribution of PAI-1 to the regulation of cell migration) plays only a limited role in the pathogenesis of the simple atherosclerotic lesions observed in the mouse.
 ...
PMID:Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. 1071 12

Atherosclerosis and the expression of monocyte chemoattractant protein-1 (MCP-1) were quantified in low density lipoprotein receptor knockout (LDLR KO) mice fed 1.25% cholesterol (study #1) or 0.2% cholesterol (study #2). In study #1 plasma total cholesterols leveled-off at 1800 mg/dl whereas plasma triglycerides remained low. In en face specimens of the aortic root and arch, intimal foam cells plus extracellular lipid particles accumulated and by 8 weeks the fatty streak surface area had rapidly expanded at both sites. In study #2, total cholesterols averaged 400 mg/dl and fatty streaks were 2-3-fold smaller compared to those in study #1. In study #3, LDLR KO mice were fed chow or 1.25% cholesterol, and immunostaining demonstrated a few Mac-2-positive intimal macrophages in mice fed chow, and during the first 10 weeks of hypercholesterolemia the number of intimal macrophages increased continuously. In chow-fed mice (0 weeks) there was little MCP-1 in the aorta. After 2 days of hypercholesterolemia intimal macrophages stained for MCP-1, and during the next 10 weeks recently recruited arterial macrophages also expressed MCP-1. Macrophage accumulation was highly correlated with MCP-1 expression. In study #4, feeding LDLR KO mice 1.25% cholesterol for 6 months produced atherosclerotic plaques at both sites and they contained a fibrous cap of smooth muscle cells, macrophage-foam cells, connective tissue and cholesterol crystals. In summary, LDLR KO mice fed cholesterol develop fatty streaks that transform into fibrous plaques. Hypercholesterolemia rapidly triggers MCP-1 expression in resident intimal macrophages, which is followed by the accumulation of more macrophages that also express MCP-1, suggesting that this chemokine may both initiate and amplify monocyte recruitment to the artery wall during early atherogenesis.
Atherosclerosis 2000 Apr
PMID:Characterization of atherosclerosis in LDL receptor knockout mice: macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE. 1072 82

Although age is a strong risk factor for atherosclerosis, it is unclear whether age may directly influence the process of atherogenesis. We, therefore, performed several studies in young (2-4 months old), mature (10-14 months old), and old (20-22 months old) mice to determine if the rate of aortic lesion formation increases with age, and whether this is related to increases in oxidative stress or vascular cell adhesion molecule (VCAM-1) expression in the aortic wall. In chow-fed low-density lipoprotein receptor-deficient (LDLR-/-) mice, plasma total cholesterol levels increased with age (250 +/- 52 mg/dl in young, 276 +/- 58 in mature, and 314 +/- 101 mg/dl in old mice). In contrast, the extent of atherosclerosis rose more rapidly, increasing from 3.6 +/- 2.7% of the aortic surface in mature mice to 18.2 +/- 8% in old mice. Plasma and tissue levels of antioxidant enzymes and molecules, as well as plasma thiobarbituric acid reactive substances and low-density lipoprotein susceptibility to oxidation, did not change with age. In a second study, VCAM-1 expression in the aortic arch and the extent of atherosclerosis in the aortic origin were significantly greater in old LDLR-/- mice than in young LDLR-/- mice. Additionally, after 1 month of a high-fat diet, which induced equally elevated plasma cholesterol levels in both young and old LDLR-/- mice, VCAM-1 expression and aortic lesion formation were still greater in old mice. The extent of atherosclerosis correlated well (r = .65,p <.01) with the expression of VCAM-1 in the aortic origin. In a final study, we measured VCAM-1 expression and atherosclerosis in young, mature, and old C57BL/6 mice, which have low plasma cholesterol levels (< or =100 mg/dl) when fed a standard chow diet. Although plasma cholesterol levels did not increase with age, old C57BL/6 mice had significantly more VCAM-1 expression in the aortic arch than did young mice. However, no lesions were observed in the aortic origin in either group. These data demonstrate that plasma cholesterol levels and VCAM-1 expression increase with age and suggest that this may contribute to the increased rate of atherosclerotic lesion formation in LDLR-/- mice. Importantly, the age-dependent increase in VCAM-1 expression does not appear to be related to plasma cholesterol levels. This study also suggests that in the absence of elevated plasma cholesterol, an increased expression of VCAM-1 alone is not sufficient for lesion formation.
 ...
PMID:Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis. 1073 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>