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 effect of simvastatin (MK-733), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the migration of cultured porcine smooth muscle cells (SMCs) was investigated in modified Boyden chambers. Platelet-derived growth factor (PDGF) stimulated the SMC migration dose dependently. MK-733 inhibited the migration response induced by PDGF with an IC50 value of 2 microM. Supplementation with mevalonate restored the migration response inhibited by MK-733 but the addition of low-density-lipoprotein (LDL) did not change the response. Another HMG-CoA reductase inhibitor, pravastatin (CS-514), also reduced the migration response. However its potency was far less than that of MK-733. MK-733 also inhibited the SMC migration stimulated by fibrinogen. These results suggest that non-sterol metabolite(s) of mevalonate, possibly prenylated proteins, are involved in a migration signaling pathway and that HMG-CoA reductase inhibitors are effective in the prevention of the formation of intimal hyperplasia in atherosclerosis.
Atherosclerosis 1992 Jul
PMID:Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-733). 164 95

With the increasing knowledge on the pathogenesis of atherosclerosis, it appears that the prevention of cardiovascular disease in the future will involve, besides risk factor correction, direct pharmacological control of processes occurring in the arterial wall. Among them, a pivotal role is played by smooth muscle cell migration and proliferation that, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates (isoprenoids) of cholesterol synthesis are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently we provided evidence that fluvastatin, simvastatin, lovastatin, but not pravastatin, dose-dependently decrease smooth muscle cell migration and proliferation, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was completely prevented by the addition of mevalonate and partially (80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through prenylated proteins--in regulating these cellular events. The present results provide evidence that HMG-CoA reductase inhibitors interfere directly with processes involved in atherogenesis--beyond their effects on plasma lipids--partially through local inhibition of isoprenoid biosynthesis.
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PMID:[The pharmacology of the statins: the evidence of a direct antiatherosclerotic action]. 856 63

With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lipids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.
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PMID:Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. 890 71

Several studies have demonstrated that any beneficial effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of the enzyme reaction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, hence effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently, we provided in vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification and endocytosis of modified lipoproteins. This in vitro inhibition was completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through a prenylated protein(s)--in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluvastatin-treated patients interfere with smooth muscle cell proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids, that could translate into a more significant prevention of cardiovascular disease.
Atherosclerosis 1998 Apr
PMID:Direct vascular effects of HMG-CoA reductase inhibitors. 969 49

Alpha-tocopherol and its esterified derivatives have been shown to be effective in reducing monocytic-endothelial cell adhesion. However, the effect of alpha-tocotrienol (alpha-T3) has not been characterized. In the present study, using human umbilical vein endothelial cells (HUVEC) as the model system, we examined the relative inhibitory effects of alpha-T3 and other vitamin E derivatives on cell surface adhesion molecule expression under TNF-alpha stimulation. Using enzyme-linked immunosorbent assay, we demonstrated that alpha-T3 markedly inhibited the surface expression of vascular cell adhesion molecule-1 in TNF-alpha activated HUVEC in a dose- and time-dependent manner. The optimal inhibition was observed at 25 micromol/l alpha-T3 within 24 h (77+/-5%) without cytotoxicity. In addition, the surface expression of intercellular adhesion molecule-1 and E-selectin were also reduced by 40+/-7 and 42+/-5%, respectively. In order to further evaluate the effects of alpha-T3 on the vascular endothelium, we investigated the ability of monocytes to adhere to endothelial cells. Interestingly, a 63+/-3% decrease in monocytic cell adherence was observed. Compared to alpha-tocopherol and alpha-tocopheryl succinate, alpha-T3 displayed a more profound inhibitory effect on adhesion molecule expression and monocytic cell adherence. This inhibitory action by alpha-T3 on TNF-alpha-induced monocyte adhesion was shown to be NF-kappaB dependent and was interestingly reversed with co-incubation with farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of adhesion molecule expression. In summary, the above results suggest that alpha-T3 is a potent and effective agent in the reduction of cellular adhesion molecule expression and monocytic cell adherence.
Atherosclerosis 2002 Jan
PMID:Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. 1175 19

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.
Atherosclerosis 2004 Feb
PMID:Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes. 1501 31

Atherosclerosis and its complications still represent the major cause of death in developed countries. Statins have revolutionized the treatment of dyslipidemia and demonstrated their ability to reduce and prevent coronary morbidity and mortality. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol synthesis. The effectiveness and rapidity of statin-induced decreases in coronary events led to the speculation that statins possess cholesterol-independent effects. Since mevalonate produced by the HMG-CoA reductase is not only the precursor of cholesterol, but also of non steroidal isoprenoid compounds, such as the farnesyl pyrophosphate and the geranylgeranyl pyrophosphate, statins also regulate the small signaling proteins, Ras and Rho. Thus, inhibition of these prenylated proteins might account for the non-lipid lowering effects of statins. In this review, we describe the numerous beneficial pleiotropic effects of statins that could modulate atherogenesis.
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PMID:Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis. 1585 54

Atherosclerosis and its complications still represent the major cause of death in developed countries. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. The effectiveness and rapidity of statin-induced decreases in coronary events led to the speculation that statins possess also cholesterol-independent effects. By the inhibition of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol synthesis, statins reduce not only cholesterol but also non steroidal isoprenoid intermediates production. Since these isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, regulate the small signaling proteins, Ras and Rho, inhibition of these prenylated proteins by statins might account for their non-lipid-related effects. In this review, we describe the numerous beneficial pleiotropic effects of statins that could modulate atherogenesis.
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PMID:Pleiotropic effects of statins in atherosclerosis: role on endothelial function, inflammation and immunomodulation. 1643 10

The molecular mechanisms underlying the relationship between low-density lipoprotein (LDL) and the risk of atherosclerosis are not clear. Therefore, detailed information on the protein composition of LDL may help to reveal its role in atherogenesis. Liquid-phase IEF has been used to resolve LDL proteins into well-defined fractions on the basis of pI, which improves the subsequent detection and resolution of low abundance proteins. Besides known LDL-associated proteins, this approach revealed the presence of proteins not previously described to reside in LDL, including prenylcysteine lyase (PCL1), orosomucoid, retinol-binding protein, and paraoxonase-1. PCL1, an enzyme crucial for the degradation of prenylated proteins, generates free cysteine, isoprenoid aldehyde and hydrogen peroxide. Addition of the substrate farnesylcysteine to lipoprotein resulted in a time-dependent generation of H(2)O(2) which was stronger in very low density lipoprotein (VLDL) than in LDL or HDL, reflecting the greater protein content of PCL1 in VLDL. Farnesol, a dead end inhibitor of the PCL1 reaction, reduced H(2)O(2) generation by VLDL. PCL1 is generated along with nascent lipoprotein, as shown by its presence in the lipoprotein secreted by HepG2 cells. The finding that an enzyme associated with atherogenic lipoproteins can itself generate an oxidant suggests that PCL1 may play a significant role in atherogenesis.
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PMID:Proteomic analysis of human low-density lipoprotein reveals the presence of prenylcysteine lyase, a hydrogen peroxide-generating enzyme. 1925 76

Oxidation of low-density lipoproteins (LDL) is thought to be a major factor in the pathophysiology of atherosclerosis. Natural antioxidants have been shown to protect LDL from oxidation and to inhibit atherogenic developments in animals. Structurally related prenylated pterocarpans, erybraedin C and bitucarpin A, and the prenylchalcone plicatin B were examined for their ability to inhibit LDL oxidation in vitro. The kinetic profile of peroxidation is characterized by the lag time of oxidation (t(lag)), the maximal rate of oxidation (V(max)) and the maximal accumulation of oxidation products (OD(max)). Specific variation of the set of kinetic parameters by antioxidants may provide important information about the mechanism of inhibitory action of a given compound. At equimolar concentrations (1 microM) the prenylated derivatives tested were found to inhibit 1 microM copper sulphate-induced oxidation of LDL (50 microg protein/ml) in accordance with the following order of activity: plicatin B>erybraedin Cbitucarpin A. Structural aspects, such as hydrogen-donating substituents, their number and arrangement in the aromatic ring moieties, and the prenyl and methoxy substituents, were investigated in order to explain the findings obtained. It is well known that the antioxidant activity of flavonoids is believed to be caused by a combination of transition metal chelation and free-radical-scavenging activities. To investigate these differences we comparatively studied the protective mechanism of plicatin B in copper-dependent or -independent LDL oxidation. The latter was mediated by 2,2'-azo-bis-(2-amidinopropane) dihydrochloride (ABAP). We measured the formation of conjugated dienes (OD(234 nm)). Plicatin B (0.2-1.5 microM) delayed the Cu(2+) (1 microM) promoted oxidation as conjugate diene formation (t(lag)) of the LDL by 45.2-123.5 min and reduced V(max) by 0.46-0.29 microM/min. In the ABAP (0.2mM) promoted LDL oxidation t(lag) increased by 67.2-110.2 min through plicatin B (0.5-2.5 microM). In experiments in which Cu(2+) concentrations increased (0.5 - 3 microM) and the amount of plicatin B (1 microM) was maintained constant, a significant decrease in t(lag) and an increase in V(max) was observed. In this study plicatin B appeared to exhibit a mixed mechanism, interfering with the formation of the radicals by chelating copper involved in the initiation/propagation reaction, but also by scavenging free hydroperoxyl radicals resulting from ABAP thermolysis. In addition, theoretical analysis indicated that plicatin B preferentially established the chelating complex with Cu(2+), because its affinity value is notably higher (by a factor of 5) than that for Cu(+).
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PMID:Protective activity of plicatin B against human LDL oxidation induced in metal ion-dependent and -independent processes. Experimental and theoretical studies. 1942 72


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