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)

The objectives of the present study were to characterize the surface expression of low density lipoprotein receptor (LDL-R) in Epstein-Barr virus transformed lymphocytes (EBV-L) and to determine the applicability of the cellular system for the study of familial hypercholesterolemia. The EBV-L subsets and LDL-R expression were determined by immuno-cytofluorimetry. The LDL-R expression in EBV-L which consisted of mostly B cells was no different among antigenic subsets. EBV-L cultured in lipoprotein deficient serum demonstrated a 9.3-fold higher LDL-R expression than primary lymphocytes. Lovastatin caused an additional 1.9-and 1.4-fold increase in EBV-L and primary lymphocytes respectively. This difference in lovastatin response is statistically significant (paired t-test, P < 0.001). 54% of the high LDL-R expression in EBV-L was related to the changes in proliferation measured as stimulation index (SI). LDL and lovastatin modulated the LDL-R expression without affecting SI. FH subjects demonstrated 2% (homozygote, n = 1) and 44.6 +/- 12.3% (heterozygotes, n = 35) in LDL-R expression of controls (n = 30). This maintenance of the FH phenotype and the intrinsically high LDL-R expression in EBV-L make the cellular system suitable for the study of FH as well as the regulation of LDL-R.
Atherosclerosis 1997 Jun
PMID:Surface expression of low density lipoprotein receptor in EBV-transformed lymphocytes: characterization and use for studying familial hypercholesterolemia. 919 67

An increased adherence of leukocytes to the vascular endothelium appears to be a crucial event in the development of atherosclerosis. The role of endothelial cell adhesion molecules is gaining increasingly interest in this context. Several studies show an influence of lipoproteins, especially low-density-lipoproteins on adhesion molecule stimulation. The aim of our study was to analyze the atherogenic potential of postprandially elevated serum triglyceride levels by investigating the impact of postprandial lipoproteins (chylomicrons (CH, isolated 4 h after a standard oral lipid load)) on the expression of E-selectin (endothelial leukocyte adhesion molecule-1, ELAM-1) and VCAM-1 (vascular cell adhesion molecule-1). In addition we used chylomicrons that had been incubated with lipoprotein lipase (50 U/ml) for 3 h (CH-LPL). The endotoxin lipopolysaccharide (LPS) served as positive control for adhesion molecule stimulation. Human umbilical vein endothelial cells (HUVEC) were incubated with the samples for 4 h and expression of E-Selectin and VCAM-1 was determined by ELISA. The expression of E-selectin was induced by LPS (530 +/- 64% compared to the basal activity (= 100%)) and by CH (342 +/- 94%); CH-LPL had no effect on E-Selectin expression. VCAM-1 expression was stimulated by LPS (395 +/- 221%) and similarly by CH-LPL (322 +/- 136%) but considerably stronger by CH (1245 +/- 324). In summary, chylomicrons induced an enhancement of the expression of both adhesion molecules, which closely resembled or even exceeded the endotoxin-induced stimulation. Interestingly, this effect was diminished or even reversed after incubation with LPL.
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PMID:Chylomicrons induce E-selectin and VCAM-1 expression in endothelial cells. 928 41

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.
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PMID:Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin. 935 54

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c-fos mRNA levels, a marker of signaling efficiency, in human SMC. Here we show that in human SMC exposed to individual growth factors (platelet-derived growth factor, epidermal growth factor, alpha-thrombin, insulin, insulin-like growth factor I (IGF-I)) and human serum, the maximal [3H]thymidine incorporation and c-fos mRNA expression are closely correlated. Only alpha-thrombin elicited overexpression of c-fos as compared with its effect on [3H]thymidine incorporation. Lovastatin efficiently inhibited [3H]thymidine uptake promoted by all mitogens tested (76-87%); however, it significantly inhibited upregulation of c-fos mRNA levels induced only by insulin (33-67%, P < 0.05) and IGF-I (31 57%, P < 0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c-fos mRNA expression induced by 4-beta-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment. Thus, in human vascular SMC, lovastatin impairs premitotic DNA synthesis induced by growth factors, but only c-fos expression promoted by insulin and IGF-I. These data indicate that statin-sensitive and -insensitive pathways seem to be involved in the regulation of c-fos in the response of human SMC to proliferative stimuli, and suggest a prominent role of isoprenylated proteins in the activation of VSMC through the IGF-I/insulin dependent pathways.
Atherosclerosis 1997 Dec
PMID:Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells. 943 Mar 71

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a novel compound, SB 204990 (the 5-ring lactone of +/-(3R*,5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid, CAS 154566-12-8), a potent inhibitor of cholesterol and fatty acid synthesis at the level of ATP-citrate lyase. APOE*3-Leiden mice were fed a saturated fat and cholesterol-rich diet supplemented with either 0.05 or 0.1% w/w of lovastatin, 0.1 or 0.2% w/w of gemfibrozil or 0.1 or 0.2% w/w of SB 204990. Lovastatin showed a dose-related decrease in plasma cholesterol levels (up to -20%) due to a lowering of LDL and HDL (low density resp. high density lipoprotein)-cholesterol (-20 and -18%, respectively), while plasma triglyceride levels were unaffected. Gemfibrozil had no effect on plasma total cholesterol levels but gave significant dose-dependent decreases in plasma (VLDL) triglyceride levels (up to -53%). SB 204990 resulted in a dose-dependent reduction of plasma cholesterol (up to -29%) by lowering VLDL, LDL and HDL-cholesterol (-50, -20 and -20%, respectively). In addition, a strong dose dependent reduction of plasma (VLDL) triglycerides up to -43% was observed with this compound. Although the effects of gemfibrozil and SB 204990 were not simply explained by changes in a single determinant of VLDL metabolism--no effects of these drugs were seen on post-heparin plasma lipoprotein lipase activity, in vivo rate of VLDL synthesis or hepatic apoC-III mRNA levels--APOE*3-Leiden mice were found to give robust hypolipidaemic responses to these test compounds. The responsiveness to hypolipidaemic therapy combined with a clear relationship between aortic lesion size and plasma cholesterol exposure, as demonstrated previously, makes this mouse an attractive model for the testing of anti-atherosclerotic properties of hypolipidaemic drugs.
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PMID:Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs. 960 83

This study examined the effects of lovastatin supplementation (25 mg/kg per day) in conjunction with an atherogenic diet (10% coconut oil (w/w), 0.05% cholesterol) on regression of pre-existing foam cells and on hepatic and intestinal LDL receptor and HMG CoA reductase mRNA levels. F1B hamsters fed the atherogenic diet had significantly greater (p < 0.0002) foam cell accumulation (10078 +/- 1452 (S.E.M.) micron2) compared to those fed a low fat, no cholesterol chow diet (64 +/- 10 micron2) or the atherogenic diet supplemented with lovastatin (1621 +/- 132 micron2). Regression of fatty streak lesions was achieved by feeding either a chow diet or supplementing the atherogenic diet with lovastatin as evidenced by the significant (p < 0.0002) reduction in foam cell accumulation in the chow regression (94 +/- 55 micron2) and lovastatin regression (48 +/- 18 micron2) groups compared to the atherogenic diet group (10078 +/- 1452 micron2). Lovastatin supplementation of the atherogenic diet induced significant upregulation of both LDL receptor and HMG CoA reductase message levels in liver and intestine compared to the chow and atherogenic diet fed groups. These data demonstrate that lovastatin supplementation of an atherogenic diet decreases foam cell accumulation and induces upregulation of hepatic and intestinal LDL receptor and HMG CoA reductase mRNA levels. Furthermore, regression of pre-existing, diet-induced fatty streak lesions can be achieved by lovastatin supplementation of an atherogenic diet or by feeding a low fat, low cholesterol chow diet. The specific effects of lovastatin on foam cell accumulation and regression and messenger RNA levels are secondary to reductions in plasma total cholesterol concentrations and do not demonstrate a direct effect of lovastatin on atherosclerotic lesions.
Atherosclerosis 1998 May
PMID:The effects of diet and lovastatin on regression of fatty streak lesions and on hepatic and intestinal mRNA levels for the LDL receptor and HMG CoA reductase in F1B hamsters. 967 70

Metabolic studies support the findings that antioxidants inhibit atherosclerosis. Treatment with vitamin E reduced both the susceptibility of low density lipoprotein cholesterol (LDL-C) to in vivo lipid peroxidation and atherosclerosis and smooth muscle proliferation. Thus the aim of present study was to examine metabolic consequences of reduced plasma LDL-C during hypolipidemic therapy and the distribution of antioxidant vitamin E. A group of 10 patients (4 men, 6 women, age 35-65y) with familial hypercholesterolaemia was treated using pravastatin (Lipostat Bristol Myers Squibb, 40 mg daily at 6:00 PM). Blood samples were examined before treatment, after 4 and 8 weeks of therapy. After ultracentrifugation, samples were analyzed for lipoprotein fractions and the content of vitamin E and cholesterol. Pravastatin reduced both total cholesterol (9.85 +/- 0.74 vs. 6.81 +/- 0.51 mmol/1; p < 0.01), LDL-C (6.42 +/- 0.45 vs. 4.51 +/- 0.45 mmol/l; p < 0.01), light LDL1-C (4.56 +/- 0.50 vs. 3.11 +/- 0.34 mmol/l; p < 0.05) and dense LDL2-C (1.86 +/- 0.27 vs. 1.42 +/- 0.17 mmol/l; ns). Serum vitamin E was reduced during hypolipidemic therapy in the fraction of total, LDL1, LDL2, and VLDL-cholesterol. However, the ratio of serum vitamin E/total serum cholesterol (4.57 +/- 0.32 vs. 5.12 +/- 0.37 mmol/l/mmol/l; p < 0.05) and ratio of LDL2-C vitamin E/LDL2-C (3.92 +/- 0.07 vs. 4.64 +/- 0.37 mmol/l/mmol/l; p = 0.08) increased in comparison to pre-treatment values. We conclude that pravastatin therapy may possess anti-atherogenic properties which involve not only its hypocholesterolemic effect, but also its favorable effects on the distribution of LDL subclasses and the content of antioxidant vitamin E in atherogenic lipoproteins.
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PMID:Hypocholesterolemic effect of pravastatin is associated with increased content of antioxidant vitamin-E in cholesterol fractions. 972 42

The endothelium contributes to the regulation of vascular tone by producing nitric oxide (NO) and the endothelium-derived hyperpolarising factor (EDHF). In hypercholesterolemia, endothelium-dependent relaxation is impaired but can be restored by treatment with lovastatin (LOVAS). We investigated the effects of LOVAS on NO and EDHF-mediated relaxation. Rabbits were fed 1% cholesterol diet for 4 weeks and 0.5%) cholesterol for the following 12 weeks (CHOL-group). The LOVAS group additionally received 10 mg of lovastatin over the last 12-week period. Experiments were performed in carotid artery rings. Relaxant responses to acetylcholine (ACh) were recorded in the presence of indomethacin. Nitro-L-arginine (NOARG, 100 microM) and potassium chloride (KCl, 35 mM) were used to differentiate between NO- and EDHF-mediated relaxations. Cholesterol impaired ACh-induced relaxations and this effect was prevented by LOVAS (control 100+/-1%, CHOL 81+/-6%, LOVAS 98+/-1%). In the presence of NOARG, relaxations to ACh were not different between the LOVAS and CHOL groups (control 78+/-4%, CHOL 64+/-6%, LOVAS 64+/-5%). When KCl was used, ACh-induced relaxations were similar in the LOVAS and control group (control 75+/-5%, CHOL 49+/-6%, LOVAS 76+/-2%). In arteries treated with NOARG and KCl together, no relaxations were observed. Relaxations of arteries from the control group were not affected by 18 h preincubation with lovastatin (10 microM). Lovastatin selectively maintains nitric oxide-mediated endothelium-dependent relaxation in hypercholesterolemic rabbit carotid arteries.
Atherosclerosis 1999 Jan
PMID:Lovastatin maintains nitric oxide--but not EDHF-mediated endothelium-dependent relaxation in the hypercholesterolemic rabbit carotid artery. 992 May 10

The vascular endothelium is the inner lining of all blood vessels and serves as an important autocrine and paracrine organ, that regulates vascular wall functions. Because of its strategic location between the circulating blood and the vascular wall, the endothelium interacts with cellular and neurohumoral mediators, thus controlling vascular contractile state and cellular composition. The vascular endothelium maintains vascular homeostasis by modulating blood vessel tone, by regulating local cellular growth and extracellular matrix deposition and by controlling hemostatic as well as inflammatory responses. One of the best characterized and most important substances released from the endothelium is nitric oxide (NO). NO is a soluble gas which is continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutively expressed nitric oxide synthase. The most important stimuli represent physical factors such as shear stress and pulsatile stretching of the vessel wall as well as circulating and locally released vasoactive substances. The endothelium can be seen as a biosensor, reacting to a large variety of stimuli and therefore maintaining adequate NO release. A large number of risk factors for atherosclerosis including hypercholesterolemia, systemic hypertension, smoking and diabetes have been associated with impaired endothelial NO-mediated vasodilation. "Endothelial dysfunction" is an early marker of atherosclerosis and may be closely related to the disease process. In acute coronary syndromes dysfunctional endothelium may trigger the devastating event of plaque rupture by promoting adhesion of leukocytes, vasoconstriction, activation of platelets and thrombos formation. Atherosclerotic blood vessels are further characterized by activation through zytokines and expression of cellular adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (E-Selectin). After adhesion to the endothelium mononuclear cells migrate to the subendothelial space to take up oxidized LDL, thus transforming into foam cells, a hall mark of early atherosclerotic lesions. A number of conditions including infection with Chlamydia pneumoniae may cause continuous activation of the endothelium and inflammation of the vessel wall. Continuous endothelial dysfunction and activation, caused by risk factors and infection, represent the basis for atherogenesis and acute coronary syndromes.
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PMID:[Endothelial dysfunction--assessment of current status and approaches to therapy]. 1009 15

Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors were shown to be effective in primary and secondary prevention of coronary heart disease. The beneficial effect of statins is generally attributed to their cholesterol lowering activity. However recent work points to additional cholesterol independent effects of these drugs on cellular signal transduction. In this study it was investigated whether HMG-CoA reductase inhibition could affect induction of the transcription factors c-Jun and c-Fos in smooth muscle cells, which play an important role in atherogenesis. SMC were preincubated for 12 h with or without lovastatin (5 microM) and subsequently stimulated with platelet derived growth factor (PDGF, 10 ng/ml) or angiotensin II (0.1 microM) for 1, 2, 4 and 12 h or with phorbol myristate acetate (100 pM) for 2 h. Stimulation in the absence of the HMG-CoA reductase inhibitor led to a significant induction of c-Jun and c-Fos. Lovastatin inhibited, PDGF-, angiotensin II- and PMA-mediated induction. Concomitant addition of mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate prevented the effects of HMG-CoA reductase inhibition resulting in rescued expression of c-Jun and c-Fos. The suppression of these transcription factors was associated with a complete growth arrest. Viability was not affected by pretreatment with the HMG-CoA reductase inhibitor. The data demonstrate that lovastatin can suppress PDGF- and angiotensin II-mediated induction of c-Jun and c-Fos protein in human SMC. This inhibitory effect may prevent activation of numerous growth factor- and cell cycle- genes. Whether these findings contribute to the effects of statins in atherosclerosis remains to be further investigated.
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PMID:Effects of HMG-CoA reductase inhibition on PDGF- and angiotensin II- mediated signal transduction: suppression of c-Jun and c-Fos in human smooth muscle cells in vitro. 1020 88


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