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 indication for HMG-CoA-reductase-inhibitors (CSE inhibitors, "statins") for primary prevention of atherosclerosis requires a careful risk/benefit calculation. For this, the PROCAM and SCORE risk scores offer validated, hands on decision support tools. In patients with manifest atherosclerosis and diabetes mellitus statins are indicated regardless of the serum cholesterol level.
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PMID:[To give or not to give? Towards the indication of CSE inhibitors ("statins")]. 1855 75

Hyperhomocysteinaemia is considered to be an independent risk factor in atherosclerosis. In the present article, we observed the effect of nitric oxide modulators on cardiovascular risk factors in mild hyperhomocysteinaemic rats. A rat model of mild hyperhomocysteinaemia was established by administering methionine (1 g/kg body weight, orally) for 4 weeks. The other groups were concomitantly treated with sodium nitroprusside (SNP) and N(omega)-nitro-l-arginine (LNNA) during the induction of hyperhomocysteinaemia. Lipid profile, total antioxidant capacity and the level of homocysteine and NO(x) (nitrates and nitrites) was examined in serum at 0 and 4 weeks. Activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the mRNA level of caveolin, P2 receptors and cardiovascular risk factors were also analysed. Stimulated lipid profile of rats by the treatment of methionine (1 g/kg body weight) reduced significantly by the treatment of SNP with methionine. LNNA increased the level of cholesterol in aorta (P < 0.05 versus group II). SNP significantly suppressed the activity of HMG-CoA reductase. The mRNA levels of caveolin (P < 0.05), P2X (P < 0.05) and P2Y (P < 0.05) showed a significant decrease in rats administered with SNP. LNNA showed significant induction in the expression of caveolin (P < 0.01) and P2Y (P < 0.01) expression. The level of P2X showed no remarkable change in animals treated with LNNA and methionine both. These data conclude that nitric oxide modulators modulate the effect of hyperhomocysteinaemia on the other cardiovascular risk factors and confirm the finding that nitric oxide plays an important role in homocysteine-induced cardiovascular diseases.
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PMID:Effects of nitric oxide modulators on cardiovascular risk factors in mild hyperhomocysteinaemic rat model. 1859 96

Aging is characterized by several metabolic changes responsible for the decline of certain functions and the appearance of age-related diseases, including hypercholesterolemia, which is the main risk factor for atherosclerosis and cardiovascular disease. Similar changes in a number of morphological and biochemical parameters were observed in rats. Caloric restriction (CR) was shown to increase longevity and prevent age-related diseases in various organisms, and to counteract the age-associated increase in plasma cholesterol. CR was thought to operate through the stimulation of the process of macroautophagy. The aim of this work was to investigate the effect of the stimulation of macroautophagy on age-associated cholesterolemia. Mature Sprague-Dawley rats were fasted overnight and given the antilipolytic agent 3,5-dimethylpyrazole (DMP; 12 mg/kg b.w. in 0.2 mL of saline, intraperitoneally). The age-related changes in cholesterol plasma level, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R) activity, and lipoperoxidation were determined. Low-density lipoprotein (LDL) receptor expression was determined by immunoblot of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)-separated liver membranes. Results show that the stimulation of macroautophagy reduces the total LDL and high-density lipoprotein (HDL) cholesterol plasma level to juvenile values, and triglycerides levels even lower. The hypocholesterolemic action of DMP requires neither the counteraction of the age-related changes in the HMG-CoA-R activation state and regulation, nor the counteraction of the age-related increase in lipoperoxidation, and only involves a restoration of the numbers of LDL receptors on liver membranes to juvenile levels.
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PMID:Stimulation of autophagy by antilipolytic drugs may rescue rodents from age-associated hypercholesterolemia. 1941 45

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are lipid-lowering agents widely employed for atherosclerosis prevention. HMG-CoA reductase blockade reduces skeletal muscle coenzyme Q(10) (CoQ(10)) levels and mitochondrial respiratory chain activities and may produce mild to severe skeletal muscle myopathy. This study investigated whether high-dose statin treatment would result in measurably decreased exercise capacity in older men and women. Maximal oxygen consumption, aerobic endurance, oxygen uptake kinetics, maximal strength, muscular power, and muscular endurance were measured before and after 12 weeks of statin treatment (simvastatin, 80 mg/day) in nine men and one woman, ages 55-76 years, with LDL-cholesterol levels >3.3 mmol/l (mean = 4.2 +/- 0.2 mmol/l). Myalgia symptoms were assessed every 4 weeks. As expected, statin treatment resulted in significant decreases in LDL- and total-cholesterol levels (P < 0.01) with no significant changes in HDL-cholesterol or triglyceride levels. No significant changes were observed in aerobic capacity, endurance, oxygen kinetics or any measures of muscle function. No subject reported symptoms of myalgia, cramps, or weakness during the study. In the absence of myalgia or myopathic symptoms, high-dose simvastatin treatment did not impair exercise capacity in hyperlipidemic older individuals. We conclude that decreases in intramuscular CoQ(10), in most patients on high dose statin treatment may not be clinically relevant, due to inter-individual variability in the degree of CoQ(10) depletion, sensitivity of muscle to decreases in CoQ(10), or both.
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PMID:High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults. 1942 52

Human aortic endothelial cells (HAEC) exposed to 50 microg/ml oxidized L-A-phosphatidylcholine B-arachidonoyl-gamma-palmitoyl (ox-PAPC) for 6h increased in interleukin-8 mRNA and protein levels. Preincubation of HAEC with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitor, (20 microM), significantly inhibited ox-PAPC-stimulated interleukin-8 mRNA and protein levels. Mevalonate (200 microM) reversed the inhibition of ox-PAPC-stimulated mRNA and protein levels by lovastatin, indicating the inhibitory effect of lovastatin was due to inhibition of mevalonate synthesis. Addition of the geranylgeraniol (GGOL, 10 microM) but not farnesol (FOL, 10 microM), reversed the inhibitory effect of lovastatin on interleukin-8 mRNA and protein levels stimulated by ox-PAPC, indicating that lovastatin exerted its effect by inhibiting stores of geranylgeranyl pyrophosphate (GGPP) which are necessary for geranylgeranylation of proteins. These results suggest a new mechanism for lovastatin in preventing atherosclerosis by inhibiting the inflammatory response that takes place in the vascular wall.
Atherosclerosis 2010 Jan
PMID:Lovastatin inhibits oxidized L-A-phosphatidylcholine B-arachidonoyl-gamma-palmitoyl (ox-PAPC)-stimulated interleukin-8 mRNA and protein synthesis in human aortic endothelial cells by depleting stores of geranylgeranyl pyrophosphate. 1959 52

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA are best known for their lipid-lowering effects but they also possess immunomodulatory properties that are, at least in part, independent of changes in serum cholesterol. Some recent clinical trials (eg. PROVE-IT) have shown that statins exert beneficial cardiovascular effects independently of the resultant level of LDL cholesterol. These "pleiotropic" effects seem to be due to inhibition of prenylation of several proteins such as the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins are able to modulate immune responses by modulating cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Over the past decade, a large number of studies reported a prominent role of inflammation and immune response in atherosclerosis, thus, the ability of statins to modulate immune-inflammatory processes could explain their cardiovascular beneficial effects beyond lipid-lowering effects. Moreover, various studies demonstrated beneficial effects of statins in inflammatory and auto-immune diseases, such as rheumatoid arthritis, multiple sclerosis and others. The purpose of this review is to summarize clinical and experimental evidence of immunomodulatory properties of these drugs, highlighting their clinical and, thus, therapeutic implications.
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PMID:Immunomodulator activity of 3-hydroxy-3-methilglutaryl-CoA inhibitors. 1966 91

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) represents an anti-atherosclerotic principle. NO bioavailability is decreased in atherosclerosis due to increased NO inactivation by reactive oxygen species and reduced NO synthesis. Various types of vascular pathophysiology are associated with oxidative stress, with NADPH oxidases as the major source of reactive oxygen species. These inactivate NO. Also, oxidative stress is likely to be the main cause for oxidation of the essential NOS cofactor, tetrahydrobiopterin (BH(4)). A lack of BH(4) leads to eNOS uncoupling (i.e., uncoupling of oxygen reduction from NO synthesis in eNOS). Based on these pathomechanisms, the therapeutic potential of a number of compounds is discussed in this review: (1) NO donors; (2) L-arginine; (3) folic acid; (4) BH(4) and its precursor sepiapterin; (5) compounds that upregulate eNOS and concomitantly maintain eNOS activity (e.g. midostaurin, betulinic acid, ursolic acid, AVE9488 and AVE3085); (6) compounds that enhance the de novo synthesis of BH(4) by stimulating expression or activity of GTP cyclohydrolase I; and (7) 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins) and drugs interrupting the renin-angiotensin-aldosterone system. Statins, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, the aldosterone antagonist eplerenone and the renin inhibitor aliskiren enhance NO bioactivity and reduce atherosclerosis progression through multiple mechanisms.
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PMID:Prevention of atherosclerosis by interference with the vascular nitric oxide system. 1975 87

Previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cells (EPCs) numbers and impairs functional activity. Atorvastatin, HMG-CoA inhibition has been showed to have protective effects on EPCs. Recent studies have demonstrated that reduced EPCs numbers and activity are associated with EPCs apoptosis. However, the protective mechanisms of atorvastatin on HHcy-induced EPCs apoptosis remain to be determined. This study was designed to examine the effect of atorvastatin on homocysteine-induced reactive oxygen species (ROS) production and apoptosis in EPCs. EPCs were isolated from peripheral blood and characterized, then challenged with Hcy (50-500 micromol/L) in the presence or absence of atorvastatin (0.01-1 micromol/L) or various stress signaling inhibitors, including mevalonate (100 micromol/L), antioxidants N-acetyl cysteine (NAC, 10 micromol/L), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI 10 micromol/L), the eNOS inhibitor N(G)mono-methyl-l-arginine LNMA (1mmol/L), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L). Apoptosis was evaluated by FACS analysis and cell viability was determined by MTT assay. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Expression of Nox4 mRNA and p-p38MAPK protein was measured by RT-PCR and Western blot analysis, respectively. Our data revealed that atorvastatin significantly suppressed Hcy-induced ROS accumulation and EPCs apoptosis. Atorvastatin also antagonized homocysteine-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Similar effects occurred with EPCs transfected with Nox4 siRNA. These findings demonstrated that atorvastatin may inhibit Hcy-induced NADPH oxidase activation, ROS accumulation, and EPCs apoptosis through Nox4/p38MAPK dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effects on EPCs function.
Atherosclerosis 2010 May
PMID:Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. 2001 84

The combination of diabetes and hyperlipidemia promotes the development of atherosclerosis. Therefore, it is important for diabetic patients to control blood fat. 3-Hydroxy-3-methylglutaryl enzyme A (HMG-CoA) reductase inhibitors (statins), like pravastatin, are frequently administered to diabetic patients for this purpose. Although the alterations of metabolic enzymes and transporters in the diabetic liver maybe change the disposition of pravastatin, the effect has not been fully investigated. In the present study, we investigated the disposition of pravastatin and the mRNA expression of transporters in the liver. Pravastatin (5 mg.kg(-1) body weight) was administered intravenously to diabetic rats, and the pravastatin concentrations in the plasma, urine, and bile were measured by high-performance liquid chromatography. Changes in the mRNA expressions of multidrug resistance-associated protein 2 (MRP2) and organic anion transporting polypeptide 2 (OATP2) in the liver were also estimated using reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the plasma pravastatin concentration was lower in the diabetic rat because the transportation of pravastatin into hepatocytes was promoted along with increased expression of OATP2. The biliary excretion ratio of pravastatin was significantly lower in the diabetic rat because the pravastatin transportation into bile was reduced along with the decreased expression of MRP2. To clarify these phenomena, the analysis of mRNA expression using real-time PCR and the measurement of the amount and the activity of proteins are necessary in future study.
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PMID:The disposition of pravastatin in a rat model of streptozotocin-induced diabetes and organic anion transporting polypeptide 2 and multidrug resistance-associated protein 2 expression in the liver. 2004 56

Hypercholesterolemia is a major risk factor for cardiovascular disease. The HMG-CoA-reductase inhibitors, statins, reduce plasma cholesterol and, as a consequence, decrease cardiovascular morbidity and mortality. Data from a subgroup analysis of the 4-S Study, however, indicate that patients with high cholesterol absorption may not benefit from statin treatment. Furthermore, there is accumulating evidence that lower hepatic synthesis and higher intestinal absorption markers are associated with increased cardiovascular risk. Therefore, prospective clinical trials are needed to evaluate whether subjects with altered cholesterol homeostasis may benefit from treatment strategies that reduce cholesterol absorption in addition to statin treatment.
Atherosclerosis 2010 Jun
PMID:Relationship between cholesterol synthesis and intestinal absorption is associated with cardiovascular risk. 2011 93


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