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)

Apolipoprotein E (apoE) is synthesized in the liver and in macrophages, and it has antiatherogenic properties that are mediated, at least in part, through the regulation of plasma cholesterol homeostasis. Previous data suggest that apoE also has antiinflammatory properties that may contribute to protection against atherosclerosis independent of its role in lipid metabolism. In this study, apoE knockout and C57BL/6 mice were stimulated with low-dose lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists. We show that apoE modulates the systemic type I inflammatory response in vivo. The proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-6, IL-12, and interferon-gamma were upregulated to a significantly greater extent in apoE-deficient mice than in wild-type mice at both the mRNA and protein levels following administration of LPS. In contrast, hypercholesterolemic low-density lipoprotein receptor/apobec-1 double knockout mice had a similar cytokine response as wild-type mice, eliminating hypercholesterolemia as a cause for the exaggerated cytokine response. Importantly, reconstitution of apoE expression in the liver of apoE-deficient mice normalized the LPS-induced plasma protein levels of IL-12p40. Furthermore, there was selective upregulation of plasma IL-12 in apoE knockout mice by a TLR3 agonist, poly I:C, but not by other TLR agonists, CpG oligonucleotide or Toxoplasma gondii antigen. This implies that apoE selectively regulates TLR4- and TLR3-mediated signaling of IL-12 production. These results indicate that apoE modulates the T helper-1-type immune response in vivo by modulating IL-12 production.
 ...
PMID:Apolipoprotein E suppresses the type I inflammatory response in vivo. 1617 87

Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.
 ...
PMID:Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction. 1637 32

The age- and sex-related levels of plasma lipids, lipoproteins and apolipoproteins in a random population sample of 2875 Hong Kong Chinese Adults (1397 men and 1478 women aged 25-74) and their implications on cardiovascular risk assessment are reported. Total cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides increased with age in both sexes. Postmenopausal women had the worst profiles. They also showed higher triglyceride and non-high density lipoprotein (non-HDL)-cholesterol and had higher percentage of values greater than the desirable limits, compared with men of the same age groups. Overall 39% of men and 29% of women had non-HDL cholesterol of 4.2 mmol/L or greater. Apolipoproteins A-I and B followed the same trends as HDL-cholesterol and LDL-cholesterol, respectively. Apolipoprotein E (apo E) allele frequencies were: epsilon2 8.7, epsilon3 80.4 and epsilon4 10.9% with the genotype having a significant effect on plasma apo E concentration (p < 0.001). Carriers of the epsilon2 allele had higher apo E values than those homozygous for E3. Lipoprotein(a) levels were higher in women than men (geometric mean 152 versus 102 mg/L, p < 0.05) and in women with FSH above versus below 40 IU/L (185 versus 136 mg/L, p < 0.05). With respect to the NCEP ATP-III 2001 guidelines, the prevalence of hyperlipidemia in the Hong Kong population approached those in high CHD prevalence Caucasian communities. Local management guidelines and community-wide programs to reduce fat intake, increase regular moderate exercise and reduce the prevalence of overweight and obesity are urgently required, and hormone replacement therapy for postmenopausal women might be warranted.
Atherosclerosis 2006 Feb
PMID:Plasma lipid, lipoprotein and apolipoprotein levels in a random population sample of 2875 Hong Kong Chinese adults and their implications (NCEP ATP-III, 2001 guidelines) on cardiovascular risk assessment. 1647 54

Elevated levels of low density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease, and recent advancements have provided evidence that carotid artery intima-media thickness (IMT) is associated with increased occurrence of cardiovascular events. Apolipoprotein E (ApoE) has been widely studied in regard to its role in lipid transport and metabolism, but the role that ApoE genetic variation plays in relation to carotid artery IMT and risk of incident coronary heart disease remains a subject of debate. In 1987-2001, the authors examined the effect of each ApoE allele (epsilon2, epsilon3, epsilon4) on LDL cholesterol and carotid IMT, as well as the association with coronary heart disease risk, in 12,491 participants of the US Atherosclerosis Risk in Communities Study. ApoE epsilon2, epsilon3, and epsilon4 allele frequencies were determined, respectively, in Whites (0.08, 0.77, 0.15) and African Americans (0.11, 0.67, 0.22). These alleles did not predict incident coronary heart disease in either racial group. The ApoE epsilon2 allele was associated with lower LDL cholesterol and the epsilon4 allele with higher LDL cholesterol in both Whites and African Americans. The ApoE epsilon2 and epsilon4 alleles were associated with carotid IMT measures in both racial groups, but, after adjusting for lipid parameters, only the epsilon4 allele was associated with carotid IMT measures in African Americans.
 ...
PMID:Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thickness but not incident coronary heart disease in 12,491 ARIC study participants. 1676 Feb 24

Atherosclerosis is the leading cause of death in industrialized countries and is becoming an increasingly worldwide risk to health. Apolipoprotein E (ApoE) is a blood circulating protein with pleiotropic atheroprotective properties that has emerged as a strong candidate for treating hypercholesterolemia and cardiovascular disease. In this review, we discuss the major developments in both viral and non-viral vectors aimed at achieving efficient delivery and sustained expression of an ApoE transgene. The technological advances in engineering viruses include cross-packaging to generate different serotypes of recombinant adeno-associated virus, and the use of multiple-deleted and helper-dependent recombinant adenovirus vectors to minimize immune responses and to package genomic loci. Non-viral ApoE delivery systems, including plasmids and cell-based therapy are also described in this review. Finally, a radical alternative to gene addition that has the potential for permanent cure in many genetic diseases--'targeted gene editing'--is reviewed. This technology uses synthetic oligonucleotides to correct underlying point mutations in situ and has been evaluated for repairing dysfunctional APOE genes.
 ...
PMID:ApoE gene therapy to treat hyperlipidemia and atherosclerosis. 1695 90

Endothelial dysfunction is characterized by abnormalities in vasoreactivity and is a marker of the extent of atherosclerosis. Cellular repair by circulating progenitor cells of ongoing vascular injury may be essential for vascular integrity and function and may limit abnormalities in vasoreactivity. Apolipoprotein E-deficient (apoE-/-) mice were splenectomized and treated with high-cholesterol diet for 5 weeks, resulting in marked impairment of endothelium-dependent vasodilation of aortic segments as compared with wild-type mice. Intravenous transfusion of 2x10(7) spleen-derived mononuclear cells (MNCs) isolated from wild-type mice on 3 consecutive days restored endothelium-dependent vasodilation in the apoE-/- mice, as measured 7, 14, and 45 days after transfusion. Histological analyses of aortic tissue identified fluorescent-labeled, exogenously applied progenitor cells that expressed the endothelial cell marker CD31 in the endothelial cell layer of atherosclerotic lesions. Progenitor cell treatment led to increased vascular nitric oxide synthase activity. Transfusion of either in vitro-differentiated Dil-Ac-LDL/lectin-positive endothelial progenitor cells, CD11b-positive (monocyte marker), CD45R-positive (B-cell marker), or Sca-1-positive (stem cell marker) MNC subpopulations significantly improved endothelium-dependent vasodilation, although these treatments were not as effective as transfusion of total MNCs. Depletion of MNCs of either CD11b-positive, CD45R-positive, or Sca-1-positive cells resulted in significant attenuation of endothelium-dependent vasodilation as compared with nondepleted MNCs; however, vasoreactivity was still significantly improved as compared with saline-treated apoE-/- mice. Intravenous transfusion of spleen-derived MNCs improves endothelium-dependent vasodilation in atherosclerotic apoE-/- mice, indicating an important role of circulating progenitor cells for the repair of ongoing vascular injury. More than 1 subpopulation of the MNC fraction seems to be involved in this effect.
 ...
PMID:Improvement of endothelial function by systemic transfusion of vascular progenitor cells. 1699 May 68

Apolipoprotein E (ApoE) alleles have been reported to affect the clinical outcome of numerous cardiovascular, neurodegenerative, and viral infectious diseases, including atherosclerosis, Alzheimer's disease (AD), hepatitis C, and HIV. The major alleles of ApoE are 2, 3, and 4. ApoE genotypes have been hypothesized to regulate many biological functions, resulting in significant changes in the onset and/or outcome (severity and duration) of several clinical conditions. Based on genetic analyses in human and animal studies using knockout (ApoE -/-) mice and mice transgenic for human 3 and 4, we present evidence that strongly suggests that the ApoE alleles can regulate the pathogenesis of ocular herpes simplex virus type 1 (HSV-1) infections. This review will summarize the major studies that support this hypothesis. Significant gender based differences in HSV-1 pathogenesis have also been reported, suggesting that hormonal regulation combined with ApoE genotype plays a significant role in HSV-1 pathogenesis. Identification of specific mechanisms in ocular HSV-1 infections related to the ApoE alleles and gender could lead to therapeutic intervention based on the properties of the apoE isoforms. While many clinical investigations have been reported and, to a lesser extent, transgenic mouse studies have been conducted, no specific mechanisms of how ApoE induces or alters clinical disease are known.
 ...
PMID:Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease. 1700 37

Apolipoprotein E-deficient mice, since their introduction in the early 1990s, have proved to be a very popular model for studying spontaneous hypercholesterolemia and the subsequent development of atherosclerotic lesions. The pathogenesis of atherosclerotic lesions in these mice mimics that found in humans on a very short time-scale. Atherosclerotic lesion development is especially prominent in the aortic arch. We have followed the progressive histopathological development of atherosclerotic lesions in the aortic arch of apolipoprotein E-deficient mice aged from 6 weeks to 18 months in 1 microm epoxy-resin sections stained with alkaline toluidine blue, which gives greatly improved resolution over wax sections. During the early stages of lesion formation, lipid-filled macrophages appear in the subendothelium, and accumulate leading to "fatty streaks". Macrophage degeneration and the formation of lipid pools are accompanied by accumulation of cholesterol deposits. Disruptions of elastic laminae of the Tunica media are accompanied by structural changes in the myocytes. More advanced lesions involve fibrous cap development, calcification of the vessel wall and progressive occlusion of the lumen. Unstable plaque may also be found. Various approaches for quantitative determination of lesion size are considered. The study provides a histopathological baseline for spontaneous atherosclerosis associated with hypercholesterolemia, which can be used in connection with experimental interventional studies on the efficacy of drugs or foodstuffs in retardation of atherosclerosis.
 ...
PMID:A mouse model for human atherosclerosis: long-term histopathological study of lesion development in the aortic arch of apolipoprotein E-deficient (E0) mice. 1700 10

Apolipoprotein E (apoE) and the low density lipoprotein receptor (LDLr) are well recognized determinants of atherosclerosis. In addition to hepatocytes, where both are highly expressed and contribute to plasma lipoprotein clearance, they are expressed in vascular cells and macrophages. In this study, we examined the effects of human apoE isoforms and LDLr levels in atherogenic pathways in primary macrophages ex vivo and atherosclerosis development after bone marrow transfer in vivo using mice expressing human apoE isoforms and different levels of LDLr expression. Increases in LDLr expression significantly increased cholesterol delivery into macrophages in culture, and the effects were more prominent with lipoproteins containing apoE4 than those containing apoE3. Conversely, increased LDLr expression reduced cholesterol efflux in macrophages expressing apoE4 but not in macrophages expressing apoE3. Furthermore, apoE3 protected VLDL from oxidation in vitro more than did apoE4. In LDLr-deficient mice expressing the human apoE4 isoform, Apoe4/4 Ldlr-/-, the replacement of bone marrow cells with those expressing LDLr increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLr. In contrast, atherosclerosis in Apoe3/3 Ldlr-/- mice, expressing the human apoE3 isoform, did not differ by the levels of macrophage LDLr expression. Our results demonstrate that apoE4, but not apoE3, in macrophages enhances atherosclerotic plaque development in mice in an LDLr-dependent manner and suggests that this interaction may contribute to the association of apoE4 with an increased cardiovascular risk in humans.
 ...
PMID:Apolipoprotein E4 in macrophages enhances atherogenesis in a low density lipoprotein receptor-dependent manner. 1723 31

Apolipoprotein E (apoE - e2, e3, e4 alleles) plays a role in the regulation of lipid metabolism, with the e4 considered to be a risk factor for coronary artery disease (CAD). We aimed to evaluate the apoE polymorphisms in Brazilians with CAD and their influence on the lipid profile and other risk factors (hypertension, diabetes mellitus, smoking). Two hundred individuals were examined: 100 patients with atherosclerosis confirmed by coronary angiography and 100 controls. Blood samples were drawn to determine apoE polymorphisms and lipid profile. As expected, the e3 allele was prevalent in the CAD (0.87) and non-CAD groups (0.81; P = 0.099), followed by the e4 allele (0.09 and 0.14, respectively; P = 0.158). The e3/3 (76 and 78%) and e3/4 (16 and 23%) were the most common genotypes for patients and controls, respectively. The lipid profile was altered in patients compared to controls (P < 0.05), independently of the e4 allele. However, in the controls this allele was prevalent in individuals with elevated LDL-cholesterol levels only (odds ratio = 2.531; 95% CI = 1.028-6.232). The frequency of risk factors was higher in the CAD group (P < 0.05), but their association with the lipid profile was not demonstrable in e4 carriers. In conclusion, the e4 allele is not associated with CAD or lipid profile in patients with atherosclerosis. However, its frequency in the non-CAD group is associated with increased levels of LDL-cholesterol, suggesting an independent effect of the e4 allele on lipid profile when the low frequency of other risk factors in this group is taken into account.
 ...
PMID:Relevance of apolipoprotein E4 for the lipid profile of Brazilian patients with coronary artery disease. 1727 55


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