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

It is well known that raised plasma triglycerides (TG) are positively linked to the development of coronary heart disease. However, triglycerides circulate in a range of distinct lipoprotein subfractions and the relative atherogenicity of these subfractions is not clear. In this study, three fractions of triglyceride rich lipoprotein (TRL) were isolated from normolipidaemic males according to their differing Svedberg flotation (S(f)) rates: chylomicron (CM, S(f)>400), very low-density lipoprotein (VLDL)-1 (S(f) 60-400) and VLDL-2 (S(f) 20-60). These fractions were incubated with THP-1 monocyte-derived macrophages for determination of cholesterol and TG accumulation, in the presence and absence of the lipoprotein lipase (LPL) inhibitor orlistat. Expression of LDL receptor related protein (LRP) and apolipoprotein B48 receptor (apoB48R) was also examined in both differentiating monocytes, and monocyte-derived macrophages, incubated with TRL. VLDL-1 caused a significantly greater accumulation of TG within macrophages compared to VLDL-2. Binding studies also tended to show a greater preference for VLDL-1. No change in expression of LRP or apoB48R was observed in fully differentiated macrophages incubated with VLDL-1, VLDL-2 or CM, although a greater expression of LRP mRNA was observed in differentiating monocytes exposed to VLDL-1, compared to those incubated with CM or VLDL-2. TG loading in response to all three TRL fractions was blocked by orlistat, suggesting that it is likely that the major pathway for uptake of TG was hydrolysis by LPL. Calculations suggested that direct uptake of particles accounts for between 12 and 25% of total TAG uptake. In conclusion, THP monocyte-derived macrophages demonstrate a preference for VLDL-1, both through the LPL pathway and by direct uptake of whole particles.
Atherosclerosis 2005 Jun
PMID:Differential uptake of subfractions of triglyceride-rich lipoproteins by THP-1 macrophages. 1591 Aug 48

Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-1) and intercellular cell adhesion molecule (ICAM- 1), strongly participate in leukocyte adhesion to the endothelium and play an important role in all stages of atherogenesis. The aim of this study was to detect and quantify the changes of endothelial expression of VCAM-1, and ICAM-1 in the vessel wall after the short-term administration of simvastatin, atorvastatin, and micro dispersed derivatives of oxidised cellulose (MDOC) in apolipoprotein-E-deficient (apoE(-/-)) mice atherosclerotic model. Hyperlipidemic apoE(-/-) mice (n = 32) received normal chow diet or diet containing simvastatin or atorvastatin 10 mg/kg/day or MDOC 50 mg/kg/day. Total cholesterol, VLDL, LDL, HDL and TAG were measured and the endothelial expression of VCAM-1 and ICAM-1 was visualized and quantified by means of immunohistochemistry and stereology, respectively. Total cholesterol levels was insignificantly lowered only in MDOC treated mice but not in mice treated with statins. ICAM-1 endothelial expression was not affected by neither simvastatin nor MDOC treatment. However, significant diminution of VCAM-1 endothelial expression was observed in both atorvastatin and MDOC treated mice. These results provide new information of potential hypolipidemic substance MDOC and its potential anti-inflammatory effects. Furthermore, we have confirmed anti-inflammatory effects of atorvastatin independent of plasma cholesterol lowering. Thus, the results of this study show potential benefit of both MDOC and atorvastatin treatment in apoE(-/-) mouse model of atherosclerosis suggesting their possible combination might be of interest.
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PMID:MDOC and atorvastatin have potential antiinflammatory effects in vascular endothelium of apoE-/- mouse model of atherosclerosis. 1630 3

The mechanisms of increased expression of toll-like receptor 4 (TLR-4) during the formation of foam cells were explored. Low density lipoprotein (LDL) was prepared by density gradient ultracentrifugation and oxidized by incubation with CuCl2. The human monocytic leukemia cell line (THP-1) was cultured in RPMI1640. The differentiation of THP-1 cells into macrophages (MPs) was induced by using myristate acetate (PMA) for 48 h. The macrophages were then incubated with oxidized LDL (ox-LDL) to generate foam cells (FCs). The mRNA and protein expression levels of human TLR-4 were detected by immunocytochemistry, Western blotting and reverse transcription polymerase chain reaction (RT-PCR). The results showed that the TLR-4 mRNA and the protein expression levels were significantly increased during the differentiation of monocytes into macrophages (P < 0.05) as well as during the formation of lipid-laden foam cells (P < 0.05). It was concluded that the upregulation of human TLR-4 gene expression during the differentiation of monocytes into macrophages and the differentiation of macrophages into foam cells could increase TLR-4 protein synthesis dramatically, which may enhance the ability of foam cells inflammation reaction in atherosclerosis.
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PMID:Mechanisms of increased expression of toll-like receptor-4 in human monocyte/macrophage-derived foam cells. 1646 49

Oxidative stress and angiogenesis are important elements in the pathogenesis of atherosclerosis and cancer. Because of its antioxidant properties, alpha-tocopherol has long proposed as prevention of diseases associated with oxidative stress. We explore whether alpha-tocopherol modulates some cell responses induced by angiogenic and proliferative stimuli. For this purpose, we evaluate the effect in human vein endothelial cells (HUVECs), of alpha-tocopherol treatment (5-40 micromol/L) for 72 h on the production of reactive oxygen species (ROS), induction of matrix metalloproteinases (MMPs), expression of vascular endothelial-cadherin (VE-cadherin) and alpha(2)-integrin, cell migration, cell proliferation, and tube formation. alpha-Tocopherol significantly inhibits intracellular ROS production induced by TNF-alpha (P < 0.01) or PMA (P < 0.001). However, alpha-tocopherol does not interfere with mRNA expression of VE-cadherin, alpha(2)-integrin, MMP-1, MMP-2, and MMP-9. Similarly, alpha-tocopherol does not modulate cell migration and capillary-like tube formation although at the concentration of 20 and 40 micromol/L it potentiated PMA-induced DNA synthesis (P < 0.05). Our results suggest that although alpha-tocopherol supplementation reduces endothelial cell oxidative stress, it does not alter the cell response to angiogenic stimuli.
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PMID:Lack of effect of alpha-tocopherol on in vitro angiogenesis. 1675 Aug 38

Scavenger receptor, class B, type I (SR-BI) mediates binding and internalization of a variety of lipoprotein and nonlipoprotein ligands, including HDL. Studies in genetically engineered mice revealed that SR-BI plays an important role in HDL reverse cholesterol transport and protection against atherosclerosis. Understanding how SR-BI's function is regulated may reveal new approaches to therapeutic intervention in atherosclerosis and heart disease. We utilized a model cell system to explore pathways involved in SR-BI-mediated lipid uptake from and signaling in response to distinct lipoprotein ligands: the physiological ligand, HDL, and a model ligand, acetyl LDL (AcLDL). In Chinese hamster ovary-derived cells, murine SR-BI (mSR-BI) mediates lipid uptake via distinct pathways that are dependent on the lipoprotein ligand. Furthermore, HDL and AcLDL activate distinct signaling pathways. Finally, mSR-BI-mediated selective lipid uptake versus endocytic uptake are differentially regulated by protein kinase signaling pathways. The protein kinase C (PKC) activator PMA and the phosphatidyl inositol 3-kinase inhibitor wortmannin increase the degree of mSR-BI-mediated selective lipid uptake, whereas a PKC inhibitor has the opposite effect. These data demonstrate that SR-BI's selective lipid uptake activity can be acutely regulated by intracellular signaling cascades, some of which can originate from HDL binding to murine SR-BI itself.
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PMID:Regulation of SR-BI-mediated selective lipid uptake in Chinese hamster ovary-derived cells by protein kinase signaling pathways. 1707 93

Obesity resides upstream of the constituents of metabolic syndromes such as diabetes, hypertension, hyperlipidemia, and arteriosclerosis. Postprandial hyperlipidemia is also implicated in atherogenesis. Therefore, factors that influence the body adiposity and the magnitude of postprandial hyperlipidemia have been intensively investigated. Diacylglycerol (DAG) oil, which is defined to contain DAG 80% (w/w) or greater in the present presentation, is an edible oil with similar taste and usability compared with conventional edible oil rich in TAG. Safety of DAG has been widely evaluated and listed as a GRAS (Generally Recognized as Safe) substance by US FDA. The aim of this review was to summarize the metabolism and nutritional functions of DAG based on the data from scientific journals and conference publications. Effect of DAG ingestion on postprandial elevations of serum lipids was investigated in several dosages, food formula, and in subjects in various conditions. Postprandial triglyceride in serum and the chylomicron fraction are significantly smaller after DAG consumption compared with TAG with a similar fatty acid composition in healthy subjects, and was remarkably reduced in subjects with insulin resistance. Long-term DAG ingestion in controlled diet or free-living condition significantly decreased body adiposity and improved type II diabetic complications. A single dose DAG consumption significantly increased fat oxidation as compared to eucaloric TAG ingestion. DAG oil consumption might be beneficial in reducing the risk factors for lifestyle-related diseases such as obesity, visceral obesity, postprandial hyperlipidemia, insulin resistance, and atherosclerosis.
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PMID:Metabolism of diacylglycerol in humans. 1739 38

Postprandial hyperlipidaemia is a common metabolic disturbance in atherosclerosis. During the postprandial phase, chylomicrons and their remnants can penetrate the intact endothelium and cause foam cell formation. These particles are highly atherogenic after modification. People in the Western world are non-fasting for most of the day, which consequently leads to a continuous challenge of the endothelium by atherogenic lipoproteins and their remnants. Furthermore, atherosclerosis is considered a low-grade chronic inflammatory disease. Many studies have shown that the process of atherogenesis in part starts with the interaction between the activated leucocytes and activated endothelium. Postprandial lipoproteins can activate leucocytes in the blood and up-regulate the expression of leucocyte adhesion molecules on the endothelium, facilitating adhesion and migration of inflammatory cells into the subendothelial space. Another inflammatory process associated with postprandial lipaemia is the activation of the complement system. Its central component C3 has been associated with obesity, coronary sclerosis, the metabolic syndrome and fasting and postprandial TAGs (triacylglycerols). Moreover, chylomicrons are the strongest stimulators of adipocyte C3 production via activation of the alternative complement cascade. A postprandial C3 increment has been shown in healthy subjects and in patients with CAD (coronary artery disease) and with FCHL (familial combined hyperlipidaemia). Postprandial lipaemia has been related to TAG and free fatty acid metabolism. All of these mechanisms provide an alternative explanation for the atherogenicity of the postprandial period.
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PMID:Postprandial inflammation and endothelial dysfuction. 1751 29

Monocyte-to-macrophage differentiation and LDL oxidation play a pivotal role in early atherogenesis. We thus questioned possible mechanisms for oxidized LDL (Ox-LDL)-induced monocyte-to-macrophage differentiation in vivo. Mouse peritoneal mononuclear cells, that were isolated 1, 2, or 3 days after Ox-LDL intraperitoneal injection, gradually exhibited the characteristic macrophage morphology, along with the expression of the cell-surface antigen CD11b. Molecular mechanisms involved in Ox-LDL-induced differentiation were further investigated in vitro using the THP-1 monocytic cell line. THP-1 cells incubated with Ox-LDL in the presence of as low as 1 ng/ml of PMA differentiated into macrophages, as evidenced by morphologic, phenotypic, and functional properties. Stimulation of monocyte-to-macrophage differentiation was selective to Ox-LDL (and not native LDL), was dependent on the extent of LDL oxidation, and required Ox-LDL internalization by the cells. These effects of Ox-LDL could be attributed to its major oxysterols, 7-ketocholesterol and 7beta-hydroxycholesterol. Finally, the stimulation of monocyte differentiation to macrophages by Ox-LDL was shown to require the M-CSF-receptor, since blocking the binding to the receptor abolished Ox-LDL/7beta-hydroxycholesterol-induced differentiation. Furthermore, Ox-LDL/7beta-hydroxycholesterol elicited tyrosine phosphorylation and activation of the M-CSF-R. We thus conclude that Ox-LDL induces monocyte differentiation to macrophages in vivo and this phenomenon involves activation of the M-CSF-receptor.
Atherosclerosis 2008 Feb
PMID:Ox-LDL induces monocyte-to-macrophage differentiation in vivo: Possible role for the macrophage colony stimulating factor receptor (M-CSF-R). 1767 37

Individuals with HIV can now live long lives with drug therapy that often includes protease inhibitors such as ritonavir. Many patients, however, develop negative long-term side effects such as premature atherosclerosis. We have previously demonstrated that ritonavir treatment increases atherosclerotic lesion formation in male mice to a greater extent than in female mice. Furthermore, peripheral blood monocytes isolated from ritonavir-treated females had less cholesteryl ester accumulation. In the present study, we have investigated the molecular mechanisms by which female hormones influence cholesterol metabolism in macrophages in response to the HIV protease inhibitor ritonavir. We have utilized the human monocyte cell line, THP-1 as a model to address this question. Briefly, cells were differentiated for 72 h with 100 nM PMA to obtain a macrophage-like phenotype in the presence or absence of 1 nM 17beta-estradiol (E2), 100 nM progesterone or vehicle (0.01% ethanol). Cells were then treated with 30 ng/ml ritonavir or vehicle in the presence of aggregated LDL for 24 h. Cell extracts were harvested, and lipid or total RNA was isolated. E2 decreased the accumulation of cholesteryl esters in macrophages following ritonavir treatment. Ritonavir increased the expression of the scavenger receptor, CD36 mRNA, responsible for the uptake of LDL. Additionally, ritonavir treatment selectively increased the relative levels of PPARgamma mRNA, a transcription factor responsible for the regulation of CD36 mRNA expression. Treatment with E2, however, failed to prevent these increases at the mRNA level. E2 did, however, significantly suppress CD36 protein levels as measured by fluorescent immunocytochemistry. This data suggests that E2 modifies the expression of CD36 at the level of protein expression in monocyte-derived macrophages resulting in reduced cholesteryl ester accumulation following ritonavir treatment.
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PMID:Estrogen prevents cholesteryl ester accumulation in macrophages induced by the HIV protease inhibitor ritonavir. 1787 45

Flaxseed lignan secoisolariciresinol diglucoside (SDG) has been reported to prevent and alleviate lifestyle-related diseases including diabetes and hypercholesterolaemic atherosclerosis. This study assesses the effect of SDG on the development of diet-induced obesity in mice and the effect of the SDG metabolite enterodiol (END) on adipogenesis in 3T3-L1 adipocytes. We compared body weight, visceral fat weight, liver fat content, serum parameters, mRNA levels of lipid metabolism-related enzymes and adiponectin in mice fed either a low-fat diet (5 % TAG), high-fat diet (30 % TAG) or high-fat diet containing 0.5 and 1.0 % (w/w) SDG for 4 weeks. Administration of SDG to mice significantly reduced high-fat diet-induced visceral and liver fat accumulation, hyperlipaemia, hypercholesterolaemia, hyperinsulinaemia and hyperleptinaemia. SDG also suppressed sterol regulatory element binding protein 1c mRNA level in the liver and induced increases in the adiponectin mRNA level in the white adipose tissue and carnitine palmitoyltransferase I mRNA level in the skeletal muscle. Differentiated 3T3-L1 adipocytes were treated with 0, 5, 10 and 20 mumol/l END and then assayed for mRNA expression of adipogenesis-related genes and DNA binding activity of PPARgamma to the PPAR response element consensus sequence. END induced adipogenesis-related gene mRNA expression including adiponectin, leptin, glucose transporter 4 and PPARgamma, and induced PPARgamma DNA binding activity in 3T3-L1 adipocytes. In conclusion, SDG induced adiponectin mRNA expression and showed beneficial effects on lipid metabolism in diet-induced obesity in mice. Flaxseed lignans are suggested to regulate adipogenesis-related gene expressions through an increase in PPARgamma DNA binding activity.
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PMID:Flaxseed lignan attenuates high-fat diet-induced fat accumulation and induces adiponectin expression in mice. 1825 24


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