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)

We have determined whether the anti-atherosclerotic effect of a 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (fluvastatin) is mediated through nitric oxide (NO) as well as affecting plasma lipids. NO related vascular responses, endothelial nitric oxide synthase (eNOS) mRNA and superoxide anion (O(2)(-)) release were examined in vascular walls of oophorectomized female rabbits fed 0.5% cholesterol chow for 12 weeks with or without fluvastatin (2 mg/kg per day). Serum lipid profile was not different between two groups. NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-L-arginine acetate (L-NMA); nitric oxide synthase inhibitor were all improved by fluvastatin treatment. Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits' arteries. Fluvastatin treatment increased cyclic GMP concentration in aorta of rabbits. eNOS mRNA expression and O(2)(-) release were measured in aorta using competitive reverse transcription-polymerase chain reaction (RT-PCR) and with lucigenin analogue, 2-methyl-3,7-dihydroimidazol [1,2-a]pyrazine-3-one (MCLA) chemiluminescence methods. eNOS mRNA in the endothelial cells of aorta was significantly up-regulated and O(2)(-) production was significantly reduced in fluvastatin treated rabbit aorta. Anti-macrophage staining area, but not anti-smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment. Conclusion, fluvastatin, a HMG-CoA reductase inhibitor, retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up-regulation of eNOS mRNA and decrease of O(2)(-) production in vascular endothelial cells, and this means that part of the anti-atherosclerotic effect of fluvastatin may be due to nonlipid factors.
Atherosclerosis 2001 Apr
PMID:A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than serum lipid lowering effects--the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action. 1125 5

We examined the relationship between plaque vulnerability and fibromuscular cap composition using hydrophilic pravastatin and lipophilic fluvastatin. WHHL rabbits aged 10 months were given pravastatin (50 mg/kg) or fluvastatin (20 mg/kg) for 52 weeks. The atherosclerotic lesions were immunohistochemically or conventionally stained and the components were analyzed with a color image analyzer. Compared with the control group, the plasma cholesterol levels were decreased by about 25% in both statin groups. Pravastatin decreased the lipid components (macrophages+extracellular lipids) in whole aortic plaques by 34% and the fibrous caps of coronary plaques by 55%. Fluvastatin decreased the fibromuscular components (smooth muscle cells+collagen fibers) in whole aortic plaques and in the fibromuscular caps of the aortic and coronary plaques. In the pravastatin group, the vulnerability index, the ratio of (lipid components)/(fibromuscular components), was decreased in whole aortic plaques by 28% and in the fibromuscular caps of coronary lesions by 61%, while the indexes were increased in the fluvastatin group. The incidence of vulnerable plaques was decreased by 74% in the coronary plaques of the pravastatin group. Our results suggest that the stability of atheromatous plaques was improved due to a decrease of the lipid components and vulnerability index of the fibromuscular cap by pravastatin.
Atherosclerosis 2001 Jul
PMID:Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHL rabbits treated with statins. 1142 6

Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated.
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PMID:The effect of fluvastatin on parameters of bone remodeling. 1144 86

Elevated Lipoprotein (a) [Lp (a)] has been reported frequently, but not consistently, to be associated with restenosis following percutaneous transluminal coronary angioplasty (PTCA). The purpose of this study was to examine the association between Lp (a) and restenosis and clinical events in the context of a multi-centre randomised restenosis [Fluvastatin Angioplasty Restenosis (FLARE)] study of patients undergoing elective PTCA with full angiographic follow up. In the FLARE trial 40 mg fluvastatin twice daily did not influence restenosis, compared with placebo, after successful balloon angioplasty, measured as late loss in 834 patients, but did reduce the risk of death or myocardial infarction. Lp (a) was not effected by fluvastatin. Lp (a) and other biochemical details were established prior to planned PTCA. Among those undergoing successful PTCA, follow up angiography was performed at 26+/-2 weeks. Clinical follow up was complete to week 40. Included in this analysis are the 823 patients who underwent successful angioplasty and had a baseline Lp (a) performed yielding 891 lesions for quantitative coronary angiography (QCA). No association was observed between Lp (a) and either quantitative markers of restenosis or binary restenosis rates. Late loss was 0.27 (SD 0.51) in the lowest quintile (Lp (a) 0-4 g/dl) compared with 0.23 (SD 0.49) (P>0.05). Elevated Lp (a) was not associated with an increased risk of individual or combined major coronary events over 40 weeks. A major adverse cardiac event (MACE) occurred in 41 (24%) of the lowest quintile and 42 (26%) of the highest (P>0.05). In conclusion, elevated Lp (a) was not associated with restenosis or clinical events following elective coronary balloon angioplasty in this randomised clinical trial and should not be considered a risk factor for post angioplasty restenosis.
Atherosclerosis 2001 Oct
PMID:The influence of plasma lipoprotein (a) on angiographic restenosis and coronary events in patients undergoing planned coronary balloon angioplasty. Ancillary analysis of the Fluvastatin Angioplasty Restenosis (FLARE) trial. 1158 25

The in vivo antioxidant effect of fluvastain, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was investigated using Watanabe heritable hyperlipidemic (WHHL) rabbits subjected to nicotine-free cigarette smoke extracts as oxidative stress. Fluvastatin was given orally at doses of 10 and 30 mg/kg per day for 5 months. The cigarette smoke extracts were prepared by bubbling the gas phase of smoke into phosphate-buffered saline and was injected daily into the rabbit ear vein. The rabbits chronically treated with the cigarette smoke extracts showed an increase in plasma lipid peroxide levels, estimated as thiobarbituric acid-reactive substances. Oxidative modification of plasma low-density lipoprotein (LDL) was assessed by anion-exchange high-performance liquid chromatographic analysis, LDL susceptibility to oxidation, LDL incorporation into macrophages and thiobarbituric acid-reactive substances levels in LDL. Treatment with fluvastatin significantly reduced these effects induced by the cigarette smoke extracts in a dose-related manner and exerted a cholesterol-lowering effect. At the end of the experiment, the cigarette smoke extracts caused accumulation of cholesteryl ester in the thoracic aorta, while fluvastatin significantly prevented this accumulation. These results indicate that fluvastatin can exert an antioxidant effect in vivo, with a strong effect on oxidative stress such as smoking, a major risk factor of atherosclerosis.
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PMID:Fluvastatin reduces modification of low-density lipoprotein in hyperlipidemic rabbit loaded with oxidative stress. 1183 52

This prospective randomized trial was designed to elucidate clinically the effect of fluvastatin on inhibiting oxidation of the low density lipoprotein (LDL) and improving the vascular endothelial function as well as its lipid-lowering effects, in comparison with pravastatin. Of 64 consecutive dyslipidemic patients, 40 patients, whose level of total cholesterol or LDL-cholesterol maintained the criteria of the hypercholesterolemia in spite of 12-week dietary therapy, were randomly assigned to receive either fluvastatin (n=20) or pravastatin (n=20). We assessed the titer of antibody against oxidized LDL (anti-Ox-LDL) as a biomarker for LDL-oxidation, and the forearm blood flow response during reactive hyperemia by venous occlusion plethysmography, which indicates the endothelium-dependent vasodilator capacity. After the 16-week lipid-lowering therapy, the anti-Ox-LDL titer significantly decreased in the fluvastatin group (P<0.01) but did not change in the pravastatin group. The percent increase in the forearm blood flow at the peak reactive hyperemia from the baseline value (%RH) significantly increased in the fluvastatin group (P<0.001) but did not change in the pravastatin group. The ratio of the %RH after the therapy over the baseline value negatively correlated with that of the anti-Ox-LDL titer (R=0.73, P<0.001) in all patients. Fluvastatin may serve as an ideal drug for reducing the risk of atherosclerosis, not only by its cholesterol-lowering effect but also by its unique effects of inhibiting LDL oxidation and improving the vascular endothelial function.
Atherosclerosis 2002 Feb
PMID:Lipid-lowering therapy with fluvastatin inhibits oxidative modification of low density lipoprotein and improves vascular endothelial function in hypercholesterolemic patients. 1184 60

In hypercholesterolemic and hypertensive patients, an increased propensity of their low-density lipoprotein (LDL) to oxidative modification has been observed. Because oxidized LDL (ox-LDL) plays a major role in atherosclerosis, the current study analyzed the anti-oxidative effect of valsartan (an angiotensin II receptor antagonist) therapy in combination with fluvastatin therapy in these patients. Administration of 40 mg/d of fluvastatin for 2 months to seven patients resulted in significant reduction in plasma total and LDL cholesterol (by 24-28%). Valsartan administration (80 mg/d for an additional 2-month period) in combination with fluvastatin did not further affect plasma cholesterol levels. Fluvastatin therapy inhibited the susceptibility of LDL to copper ion-induced oxidation, as shown by prolongation of the lag time by 22% and by a reduction of thiobarbituric acid-reactive substances (TBARS) levels by 14%, as compared with the patient's LDL baseline oxidation. The addition of valsartan to fluvastatin resulted in a further 17% prolongation of the lag time and in an additional reduction of 21% in TBARS levels. In a parallel study, the LDL from eight patients who were first treated with 80 mg/d of valsartan for 2 months demonstrated reduced susceptibility to copper ion-induced oxidation, as observed by prolongation of lag time by 23% and reduction in TBARS levels by 19%, compared with the baseline values. The administration of 40 mg/d of fluvastatin for an additional 2 months in combination with valsartan, however, demonstrated no further inhibitory effect on LDL oxidation. The anti-oxidative properties of fluvastatin and valsartan against LDL oxidation were also demonstrated in vitro and the combination of both drugs was shown to have an additive effect. Valsartan therapy in hypercholesterolemic and hypertensive patients has an additive anti-oxidative effect to that of fluvastatin therapy. This may be related both to the anti-oxidative properties of valsartan and to the blocking of angiotensin II-induced oxidative stress.
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PMID:Valsartan therapy has additive anti-oxidative effect to that of fluvastatin therapy against low-density lipoprotein oxidation: studies in hypercholesterolemic and hypertensive patients. 1207 74

Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid as well as lipid-lowering mechanisms, but their anti-inflammatory effects on the vascular tissue have not been fully elucidated. We investigated the effects of fluvastatin on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Addition of fluvastatin decreased IL-6 synthesis in VSMCs in a time (0-24 hours)- and dose (10(-8)-10(-5) mol/L)-dependent manner. Fluvastatin also decreased IL-6 mRNA expression in VSMCs. The effects of fluvastatin on IL-6 expression were completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not squalene. Inhibition of Rho by C3 exoenzyme or Rho kinase by Y-27632 significantly decreased IL-6 expression in VSMCs. In conclusion, fluvastatin decreases IL-6 synthesis in human VSMCs through inhibition of Rho pathway. These findings suggested that reduction of IL-6 expression by statins may partially explain their therapeutic effects in patients with coronary artery disease.
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PMID:HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. 1209 Sep 4

Proteoheparan sulphate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. As a result of electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques suggesting that high-density lipoprotein (HDL) has a high binding affinity and a protective effect on interfacial heparan sulphate proteoglycan layers with respect to low-density lipoprotein (LDL) and Ca2+ complexation. Low-density lipoprotein was found to deposit strongly at the proteoheparan sulphate-coated surface, particularly in the presence of Ca2+, apparently through complex formation 'proteoglycan-LDL-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulphate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a 'nanoscopic' level under close to physiological conditions. In particular, Ca2+-promoted LDL deposition and the protective effect of HDL even at high Ca2+ and LDL concentrations agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis. Considering this, the system was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL plasma fraction from a high risk patient with dyslipoproteinaemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. Fluvastatin, whether applied to the patient (one single 80 mg slow release matrix tablet) or acutely in the experiment (2.2 micromol L-1), markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca2+ concentrations used. This action resulted without any significant change in lipid concentrations of the patient. Furthermore, after ternary complex build-up, fluvastatin, similar to HDL, was able to reduce nanoplaque adsorption and size. These immediate effects of fluvastatin have to be taken into consideration while interpreting the clinical outcome of long-term studies.
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PMID:Biosensing of arteriosclerotic nanoplaque formation and interaction with an HMG-CoA reductase inhibitor. 1235 73

Sterol regulatory elements binding factor-1a (SREBF-1a) and SREBF cleavage activating protein (SCAP) regulate lipids homeostasis. Polymorphisms in SREBF-1a and SCAP could affect plasma levels of lipids and risk of atherosclerosis. We determined association of SREBF-1a -36del/G and SCAP 2386A/G genotypes with plasma levels of lipids, severity and progression/regression of coronary atherosclerosis, and response to treatment with fluvastatin in a well-characterized Lipoprotein Coronary Atherosclerosis Study population. Plasma lipids and quantitative indices of coronary atherosclerosis were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo in 372 subjects. Fluvastatin reduced plasma levels of total cholesterol by 16%, LDL-C by 25%, and ApoB by 16% and increased plasma levels of HDL-C by 9% and apoA-1 by 7%. Distributions of SREBF-1a SCAP genotypes were 60 GG, 172 del-G and 140 del-del and 88 GG, 188 GA and 96 AA, respectively. There were no significant differences in baseline plasma levels of lipids or indices of severity of atherosclerosis among the genotypes of each gene. There was a strong graded genotype-treatment interaction between SREBF-1a genotypes and change in apoA-I levels in response to fluvastatin (16.5% increase in GG, 10.5% in del/G, and 0.4% in del/del groups). Modest interactions between SREBF-1a genotypes and changes in HDL-C, and apoC-III levels in response to fluvastatin were also present. No genotype-treatment interaction for progression or regression of coronary atherosclerosis was detected. There were no significant interactions between SCAP genotypes and response to therapy. Thus we detected a strong graded interaction between SREBF-1a -36del/G genotypes and response of plasma apoA-I to treatment with fluvastatin.
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PMID:Effects of SREBF-1a and SCAP polymorphisms on plasma levels of lipids, severity, progression and regression of coronary atherosclerosis and response to therapy with fluvastatin. 1243 50


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