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)

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.
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PMID:Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study. 1746 Jan 78

Little is known of the relationship between plaque rupture and adaptive geometric remodelling, especially in the context of unstable atherosclerosis. We have assessed remodelling in the proximal brachiocephalic arteries of fat-fed apoE (apolipoprotein E)-knockout mice. The rate of vessel expansive remodelling is similar in vessels with plaques and without plaques, suggesting that the presence of plaque is not necessary for remodelling to occur. In vessels with plaques, the degree of expansive remodelling was strongly associated with the stability of the plaque. Vessels with stable plaques (i.e. with neither buried fibrous caps nor acute plaque ruptures) showed no expansion, whereas those with evidence of plaque rupture expanded at a significant rate. Vessels with stable plaques suffered significant loss of lumen over time, but those with unstable plaques maintained lumen area over time. Pravastatin treatment of male apoE-knockout mice caused a 5-fold increase in fibrous cap thickness and, although it did not influence overall rates of vessel remodelling, it significantly increased both the amount of vessel expansion and the period of time between plaque ruptures, suggesting that it increases the ability of the plaque to resist the rupturing force caused by vessel expansion. These results suggest that vessel expansion in brachiocephalic arteries of fat-fed apoE-knockout mouse does not require the presence of plaque. When a plaque is present, the outward remodelling force is exerted across its cap: vessels with smaller outward remodelling forces cannot overcome the strength of the cap, and the plaque remains stable. When the remodelling force is greater than the strength of the cap, the plaque ruptures. Thus plaque rupture can be viewed as a consequence of vessel remodelling. Interventions that strengthen the plaque, such as pravastatin therapy, do not alter remodelling parameters but instead allow for more outward remodelling before a rupture is caused.
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PMID:Is there life after plaque rupture? 1795 38

Pravastatin is reported to increase the adiponectin level in humans, but the mechanism remains unclear. We examined plasma and gene expressions of adiponectin, tumor necrosis factor (TNF)-*, interleukin (IL)-6 and protein carbonyl level, an indicator of oxidative stress, in visceral and subcutaneous adipose tissue from 32 patients with coronary artery disease undergoing coronary artery bypass grafting (CABG). Fourteen patients with serum LDL-cholesterol level >100mg/dl were treated with pravastatin at 10mg/day for 2 months before CABG (Statin), and the other 18 with LDL-cholesterol <or=100mg/dl were not (Control). The plasma adiponectin level was higher in the Statin than the Control group (P<0.05), but TNF-* and IL-6 levels were not different. Adiponectin gene expression in visceral tissue was 3-fold higher in the Statin than the Control group (P<0.01), but was not different in subcutaneous tissue. TNF-* and IL-6 gene expressions in each tissue were not different between the 2 groups. Protein carbonyl levels in plasma and visceral tissue were lower in the Statin than the Control group (both, P<0.05). Thus, adiponectin expression and generation in visceral adipose tissue is increased in men with coronary artery disease treated with pravastatin. Pravastatin-initiated attenuation of oxidative stress could be involved.
Atherosclerosis 2008 Aug
PMID:Increased adiponectin synthesis in the visceral adipose tissue in men with coronary artery disease treated with pravastatin: a role of the attenuation of oxidative stress. 1816 19

Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5783 elderly participants in Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p<0.001) lower levels of LDL C (mean, -10%), no difference in LDL C lowering response to pravastatin, and a non-significant 19% unadjusted and 9% adjusted decreased risk of vascular disease at baseline, with no on trial effect. Moreover, 6.0% were carriers of the G allele at E670G with no significant relationships with baseline LDL C, response to pravastatin, or vascular disease risk being observed. Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.
Atherosclerosis 2008 Sep
PMID:Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. 1826 90

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.
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PMID:Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study. 1850 81

1. The beneficial effects of pravastatin, beyond that of lowering cholesterol in atherosclerosis, include reducing the action of interferon (IFN)-gamma. Interferon-gamma activates the signal transducer and activator of transcription 1 (STAT1), but it is unclear whether the inhibitory effect of pravastatin in atherosclerosis is via modulation of the IFN-gamma/STAT1 pathway. Thus, the aim of the present study was to determine whether the action of pravastatin in preventing aortic atherosclerosis by attenuation of IFN-gamma action is dependent on STAT1. 2. Male apolipoprotein E-knockout (apoE(-/-)) mice were fed a diet containing 1.25% cholesterol (w/w). Mice were divided into two groups, one of which was supplemented with pravastatin (80 mg/kg per day). Male C57BL/6J mice were fed a normal diet and served as the control group (n = 12 per group). 3. Atherosclerotic lesions in the aortic root were assessed by staining sections haematoxylin and eosin. Serum concentrations of IFN-gamma and IFN-gamma mRNA expression in the thoracoabdominal aorta were determined by ELISA and real-time quantitative polymerase chain reaction methods, respectively. Expression of phosphorylated STAT1 (pSTAT1), interferon regulating factor (IRF)-1 and suppressors of cytokine signalling 1 (SOCS1) was determined in the thoracoabdominal aorta using Western blot analysis. 4. After 8 weeks, pravastatin treatment significantly prevented the formation of atherosclerotic lesions (P < 0.05) and reduced serum IFN-gamma concentrations (P < 0.05) and levels of IFN-gamma mRNA within the aorta (P < 0.01). Pravastatin significantly decreased the expressions of pSTAT1 and IRF-1 within the aorta and significantly increased expression of SOCS1. 5. These results suggest that the actions of pravastatin in attenuating the action of IFN-gamma and subsequently preventing aortic atherosclerosis may depend, at least in part, on modulation of STAT1 activity. This providing us with a new therapeutic approach and a clearer insight into the clinical benefits of pravastatin.
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PMID:Pravastatin attenuates interferon-gamma action via modulation of STAT1 to prevent aortic atherosclerosis in apolipoprotein E-knockout mice. 1901 8

Secretory phospholipase A2 (sPLA2) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE(-/-) mice were investigated. Male apoE(-/-) mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-alpha actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by approximately 75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.
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PMID:The synergistic inhibition of atherogenesis in apoE-/- mice between pravastatin and the sPLA2 inhibitor varespladib (A-002). 1902 66

The plasma level of adiponectin (CAS 1070484-33-1), known as an anti-atherogenic adipocytokine, inversely correlates with the progression of atherosclerosis. The reported effects of statins on the serum level of adiponectin include significant increases in the adiponectin levels caused by pravastatin (CAS 81131-70-6). In this study, increasing the dosage of pravastatin was investigated to determine whether it had a clearly favorable effect on the adiponectin level in hypercholesterolemic patients. A total of 26 mild hypercholesterolemic and hypertensive patients were enrolled in this study. The patients were initially treated with pravastatin 10 mg/day for 6 months or more, and then increased to pravastatin 20 mg/day. Serum adiponectin, cholesterol fractionated components, and lipoprotein components were evaluated after 6 months. Increasing the dose of pravastatin from 10 to 20 mg/day caused the low-density lipoprotein cholesterol levels to decrease (from 130 to 104 mg/dL, p < 0.001), and thereafter the serum adiponectin levels, particularly the high-molecular-weight adiponectin levels significantly increased (from 10.9 to 12.6 microg/mL, p = 0.022; from 6.6 to 7.6 microg/mL, p = 0.022, respectively). Pravastatin increased the serum adiponectin level after increasing the dosage from 10 to 20 mg/day. It remains possible, however, that the difference was due not only to pharmacologic effects, but also to other specific characteristics such as the subject characteristics, viz.; race, body size, high-density lipoprotein cholesterol, etc.
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PMID:Effects of increasing the dose of pravastatin on serum adiponectin level in Japanese mild hypercholesterolemic and hypertensive patients. 1985 91

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

Reciprocal relationships between endothelial dysfunction and insulin resistance suggest that therapies improving endothelial dysfunction will simultaneously improve insulin sensitivity and other metabolic parameters. However, previous studies with some statins either did not alter insulin sensitivity or promoted insulin resistance despite significant improvements in endothelial dysfunction and decreases in circulating pro-inflammatory markers. This may be due to pleiotropic or off-target effects of some statins to cause insulin resistance by diverse mechanisms unrelated to endothelial dysfunction. Indeed, there is evidence of other differential metabolic actions of distinct statins including effects on hydroxymethylglutaryl-CoA reductase inhibition, isoprotenoid synthesis, calcium release, glucose transport, insulin secretion, and/or insulin resistance. Pravastatin increases expression of adiponectin mRNA, enhances adiponectin secretion, increases plasma levels of adiponectin, and enhances insulin sensitivity in mice and humans. Clinical studies including large scale randomized controlled trials demonstrate potential differences between individual statins, with pravastatin promoting risk reduction for new onset of diabetes. Conversely, other statins including atorvastatin, rosuvastatin, and simvastatin all promote significant increase in this risk. Given the frequent concordance of metabolic diseases including diabetes, obesity, and metabolic syndrome with cardiovascular diseases associated with hyperlipidemia, it is important to understand the potential metabolic risks and benefits of therapies with distinct statins. In this review, we discuss these differential effects of statins on metabolic homeostasis and insulin sensitivity.
Atherosclerosis 2011 Mar
PMID:Differential metabolic effects of distinct statins. 2113 Apr 54


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