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PubMed2001

Essential fatty acids as possible mediators of the actions of statins.

Statins and polyunsaturated fatty acids have similar actions: both enhance endothelial nitric oxide synthesis, inhibit the production of pro-inflammatory cytokines, lower cholesterol levels, prevent atherosclerosis and are of benefit in coronary heart disease, stroke and osteoporosis. Statins enhance the conversion of linoleic acid and eicosapentaenoic acid to their long chain derivatives. Animals with essential fatty acid deficiency show an increase in HMG-CoA reductase activity, which reverts to normalcy following topical application of linoleic acid. Similarly to statins, polyunsaturated fatty acids also inhibit HMG-CoA reductase activity. In view of the similarity in their actions and as statins influence essential fatty acid metabolism, it is suggested that essential fatty acids and their metabolites may serve as second messengers of the actions of statins.

Alzheimer Disease↗
PubMed2003

The statins: multifunctional antithrombotic and antineoplastic drugs.

Statins are approved by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia and have shown remarkable activity in preventing cardiovascular morbidity and mortality. The versatility of statins is increasingly being appreciated, however, and lowering cholesterol is only one attribute among many shared by this class of drugs. Most statins appear to have antithrombotic activity that is unrelated to the ability to reduce cholesterol levels, and several have significant antitumor effects. This article reviews the laboratory and clinical evidence that statins have antithrombotic and anticancer activity, discusses the ways in which these two activities intersect, and proposes novel uses for statins for the treatment of conditions other than hypercholesterolemia.

Antineoplastic Agents↗
PubMed2004

Statins effect on smooth muscle cell proliferation.

Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents.

Animals↗
PubMed2004

Anti-inflammatory properties of statins.

Increasing clinical and experimental evidence indicates that some beneficial effects of statins, known as efficient therapeutic agents in cardiovascular disease treatment, may result from their ability to modulate vascular and endothelial cell gene expression by mechanisms independent of cholesterol reduction. It has been shown that statins exhibit direct anti-inflammatory properties via inhibition of proinflammatory cytokine and chemokine secretion, as well as through adhesion molecule expression on leukocytes. Another important mechanism by which statins may modulate the immune response is inhibition of interferon gamma-induced expression of class II major histocompatibility complexes. Class II major histocompatibility complex expression is central to immune regulation in T cell-mediated autoimmune diseases, indicating a potential beneficial role of statins in these pathologies. Indeed, promising new preclinical data indicate that statins might be useful in the treatment of multiple sclerosis and rheumatoid arthritis.

Animals↗
PubMed2002

Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. HMGR is the target of compounds (HMGR inhibitors, commonly referred to as statins) that are very effective in lowering serum cholesterol levels. These inhibitors have K(i) values in the nanomolar range and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of this enzyme in complexes with 6 different statins (compactin, simvastatin, fluvastatin, cerivastatin, atorvastatin, and rosuvastatin). The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. The nicotinamide binding pocket of NADP(H) (the second substrate of the enzyme) is unoccupied by the inhibitor molecules. Near the C-terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. The flexibility of these residues is critical for binding with statins; if ordered, they would sterically hinder such binding.

Animals↗
PubMed2003

Treating dyslipidemia with statins: the risk-benefit profile.

BACKGROUND: Coronary heart disease (CHD), the result of coronary atherosclerosis, is the largest single killer of Americans. Central to the pathogenesis of atherosclerosis are the deposition and retention of cholesterol in the arterial walls. Lipid modification, therefore, is key to CHD prevention. METHODS: Data from trials evaluating the safety and efficacy of several pharmacologic agents for dyslipidemia were thoroughly reviewed. RESULTS: Agents such as bile acid sequestrants, fibric acids, and nicotinic acid have a role in treating dyslipidemia. However, statins are the safest and most effective of the lipid-modifying drugs, reducing the incidence of CHD by as much as 21% to 43%. Despite the overall safety and efficacy of these agents, many patients undergoing statin therapy fail to achieve the treatment goals specified in the National Cholesterol Education Program Adult Treatment Panel III guidelines, often because of suboptimal use, tolerability problems, or lack of compliance. Although adverse effects of statins are generally mild and transient, more serious adverse effects, including myotoxicity, liver toxicity, and rhabdomyolysis, are still possible with statin monotherapy and are more common in patients receiving concomitant therapy with other drugs metabolized by the cytochrome P-450 enzyme system. CONCLUSIONS: Because of the overall safety and efficacy of the statins, more patients with or at risk for CHD should be receiving aggressive therapy to lower low-density lipoprotein cholesterol levels and reduce CHD risk.

Atorvastatin↗
PubMed2004

Effect of 12-month statin therapy on antioxidant potential of LDL and serum antioxidant vitamin concentrations.

BACKGROUND: Statins are known to cause short-term reduction in serum lipid-soluble antioxidant concentrations, but their long-term effects are not known. AIM: We randomised 104 subjects with CHD and hypercholesterolaemia to receive either atorvastatin or simvastatin treatment for 52 weeks and measured the antioxidant potential of LDL and serum antioxidant vitamin concentrations. METHOD: Initial daily dose for both statins was 20 mg. RESULTS: LDL antioxidant capacity and serum alpha-tocopherol, gamma-tocopherol and beta-carotene concentrations decreased by 22%-35% with both statins during the first 12 weeks' therapy (P < 0.01 for all). After 52 weeks' therapy, the concentrations of serum gamma-tocopherol in the simvastatin group and serum beta-carotene in both treatment groups returned to baseline levels, while the concentrations of serum gamma-tocopherol in the atorvastatin group and LDL anti-oxidant capacity and serum alpha-tocopherol in both treatment groups remained reduced (P < 0.001 for all). The LDL antioxidant capacity:LDL-cholesterol and the serum alpha-tocopherol:LDL-cholesterol ratios were significantly elevated with both statins after 12 and 52 weeks (P < 0.001 for all). Statistically significant increases were also observed for corresponding ratios of the less abundant vitamins gamma-tocopherol and beta-carotene. CONCLUSIONS: Some of the decreases in serum lipid soluble antioxidant vitamins reported in short-term statin interventions may become attenuated when therapy continues longer. The relative antioxidant capacity of LDL particles increased during the 52-week treatment, suggesting that the oxidation resistance of LDL particles did not become impaired and that their atherogenicity did not increase.

Atorvastatin↗
PubMedDate not supplied

The HMG-CoA reductase pathway, statins and angioprevention.

Angiogenesis is one of the earliest and essential phenotypes acquired by tumors during carcinogenesis and thus might be a potential target for chemoprevention. Key to developing antiangiogenic chemoprevention is to identify new molecular targets and effective angiogenesis inhibitors. HMG-CoA reductase inhibitors, or statins, were originally designed to reduce cholesterol biosynthesis and have been extensively used as prevention drugs against hyperlipidemia and cardiovascular conditions. Recent research has found that statins promote endothelial death and inhibit experimental angiogenesis induced by growth factors or tumor, laying a foundation for developing statin-based angiopreventive strategies. This article reviews the biological effects of statins on endothelial cells and angiogenesis, possible underlying mechanisms and perspectives on future application of statins in preventing pathological angiogenesis.

Animals↗
PubMed1994

Statin--a novel marker of nonproliferation. Expression in nonneoplastic lymphoid tissues and follicular lymphomas.

Statin is a 57 kDa nuclear protein exclusively found in noncycling cells. Its expression in hematolymphoid cells had not been examined previously. The authors studied statin immunoreactivity in nonneoplastic lymphoid tissues from 26 lymph nodes, 3 tonsils, and 2 spleens. Statin was detected primarily in small lymphoid cells and histiocytes, along with such accessory elements as fibroblasts and endothelial cells. The distribution of positive cells showed an inverse correlation with the proliferative activity of the various lymphoid compartments. Statin labeling was also quantified in 15 follicular lymphomas and compared with that in hyperplastic follicles. Although reactivity in benign germinal centers was less than that in neoplastic follicles, this difference did not prove statistically significant. Statin provides an alternative to proliferation-associated parameters, such as Ki-67 and proliferating cell nuclear antigen, in the analysis of hematolymphoid processes and may be helpful in the dissection of their kinetic heterogeneity.

Cell Cycle Proteins↗
PubMed2005

Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells.

Although statins are lipid-lowering drugs that block cholesterol biosynthesis, they exert immunomodulatory, anti-inflammatory, anti-angiogenic and anti-proliferative functions by reducing the isoprenylation of proteins involved in cell signal transduction such as Ras and RhoA. In this study, we provide evidence that several natural (lovastatin, simvastatin and pravastatin) and synthetic (cerivastatin and atorvastatin) statins exert a cytotoxic effect on human T, B and myeloma tumor cells by promoting their apoptosis. Dissimilar susceptibility to apoptosis has been detected in these lines, presumably in relation to the altered expression of proteins involved in the regulation of cellular signals. Cerivastatin promptly activated the cell death even in doxorubicin resistant cell lines such as MCC-2, whereas pravastatin, a hydrophilic compound, failed to induce any effect on either proliferation or apoptosis. The statin-induced apoptotic pathway in these cell lines was presumably regulated by altered prenylation of either Ras or RhoA, as measured by the defective membrane localization of these small GTPases. In addition the cell proliferation was rescued by both farnesylpyrophosphate (FPP) and geranyl-geranylpyrophosphate (GGPP), whereas no effect was obtained with squalene, a direct precursor of cholesterol. Statins primed apoptosis through its intrinsic pathway involving the mitochondria. In fact, we observed the reduction of mitochondrial membrane potential and the cytosolic release of the second mitochondria-derived activator of caspases (Smac/DIABLO). The apoptotic pathway was caspase-dependent since caspases 9, 3 and 8 were efficiently activated. These results support the potential use of statins in association with conventional treatment as apoptosis-triggering agents in these tumors.

Apoptosis↗
PubMed2005

Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction?

AIMS: The study evaluates the effect of statin therapy on the prognostic impact of non-sustained ventricular tachycardia (NSVT) occurring after acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: From the German Acute Coronary Syndrome Registry (ACOS), 3137 patients with STEMI and in-hospital Holter monitoring were analysed. Three hundred and forty-six (11.0%) patients had NSVT. When compared with patients with no documented NSVT, patients with NSVT were older, more often had myocardial infarction in their history, diabetes mellitus, and an ejection fraction <40%. Regarding frequency of drug application, medication at discharge did not (beta-blockers, ACE-inhibitors, amiodarone) or only slightly (acetylsalicylic acid, statins, and sotalol) differ between both groups. Multivariable analysis of 1 year mortality, adjusted for age, gender, diabetes, reperfusion therapy, ejection fraction <40%, and beta-blocker therapy showed the following results: In patients without statin treatment and no NSVT, 1 year mortality after STEMI was 9.2%, but increased to 25.0% [odds ratio (OR) 3.02; 95% confidence interval (CI) 1.47-6.20], if NSVT were present. In patients on statin treatment and no NSVT, 1 year mortality was only 3.2%, and in the presence of NSVT 1 year mortality was not significantly increased anymore (5.3%; OR 1.03; 95% CI 0.55-1.92). CONCLUSION: After STEMI, only in patients not on statin treatment, the occurrence of NSVT is associated with a significant and marked increase in 1 year mortality.

Aged↗
PubMed2006

Chronic pre-treatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction.

AIMS: Early statin treatment has beneficial effects on prognosis after acute coronary syndrome. The no-reflow phenomenon determines the prognosis after acute myocardial infarction. We investigated the effects of statin treatment before admission on the development of the no-reflow after infarction. METHODS AND RESULTS: We performed intracoronary myocardial contrast echocardiography in 293 consecutive patients with acute myocardial infarction undergoing successful primary percutaneous coronary intervention. There were no significant differences in the incidence of the no-reflow between the patients with and without hypercholesterolaemia. The 33 patients receiving chronic statin treatment before admission had lower incidence of the no-reflow than those without it (9.1 and 34.6%, P=0.003). They also showed better wall motion, smaller left ventricular dimensions, and better ejection fraction at 4.9+/-2.2 months later. Multivariable logistic regression analysis revealed that statin pre-treatment was a significant predictor of the no-reflow along with anterior wall infarction, ejection fraction on admission, and additional ST-elevation after reperfusion, whereas total cholesterol was not. CONCLUSION: Chronic pre-treatment with statins could preserve the microvascular integrity after acute myocardial infarction independent of lipid lowering, leading to better functional recovery.

Adult↗
PubMed2002

Reduction of new coronary events and new atherothrombotic brain infarction in older persons with diabetes mellitus, prior myocardial infarction, and serum low-density lipoprotein cholesterol >/=125 mg/dl treated with statins.

BACKGROUND: We report the incidence of new coronary events and new atherothrombotic brain infarction (ABI) in older men and women with diabetes mellitus, prior myocardial infarction, and a serum low-density lipoprotein (LDL) cholesterol of >/=125 mg/dl treated with statins and with no lipid-lowering drug. METHODS: The incidence of new coronary events and of new ABI was investigated in an observational prospective study of 529 diabetics, mean age 79 +/- 9 years, with prior myocardial infarction and a serum LDL cholesterol of >/=125 mg/dl treated with statins (279 persons or 53%) and no lipid-lowering drug (250 persons or 47%). Follow-up was 29 +/- 18 months. RESULTS: At follow-up, the stepwise Cox regression model showed that after controlling for other risk factors, the use of statins was associated with a 37% significant independent reduction in the incidence of new coronary events and with a 47% significant independent reduction in the incidence of new ABI. CONCLUSIONS: Use of statins was associated with a 37% significant, independent reduction in new coronary events and a 47% significant, independent reduction in new ABI in older men and women with diabetes mellitus, prior myocardial infarction, and a serum LDL cholesterol of >/=125 mg/dl. Elderly diabetics with prior myocardial infarction and increased serum LDL cholesterol should especially be treated with statins.

Aged↗
PubMed2002

Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol >or=125 mg/dl treated with statins versus no lipid-lowering drug.

BACKGROUND: We report the incidence of new atherothrombotic brain infarction (ABI) in older men and women with prior myocardial infarction and a serum low-density lipoprotein (LDL) cholesterol of >or=125 mg/dl treated with statins and with no lipid-lowering drug. METHODS: The incidence of new ABI was investigated in an observational prospective study of 1410 men and women, mean age 81 +/- 9 years, with prior myocardial infarction and a serum LDL cholesterol of >or=125 mg/dl treated with statins (679 persons or 48%) and with no lipid-lowering drug (731 persons or 52%). Follow-up was 36 +/- 21 months. RESULTS: At follow-up, the stepwise Cox regression model showed that significant independent predictors of new ABI were age (risk ratio = 1.04 for a 1-year increase in age), cigarette smoking (risk ratio = 3.5), hypertension (risk ratio = 3.1), diabetes mellitus (risk ratio = 2.3), initial serum LDL cholesterol (risk ratio = 1.01 for each 1 mg/dl increase), initial serum high-density lipoprotein cholesterol (risk ratio = 0.97 for each 1 mg/dl increase), prior stroke (risk ratio = 2.5), and use of statins (risk ratio = 0.40). The Cochran-Armitage test showed a trend in the reduction of new ABI in persons treated with statins as the level of serum LDL cholesterol decreased ( p <.0001). CONCLUSIONS: Use of statins caused a 60%, significant, independent reduction in new ABI in older men and women with prior myocardial infarction and a serum LDL cholesterol of >or=125 mg/dl.

Aged↗
PubMed2004

HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage.

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to have anticancer effects in many models. We have investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, while mRNA levels were unchanged. Furthermore, pravastatin was found to induce phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to active Mdm2 and has been shown to increase its ubiquitin ligase activity and lead to increased p53 degradation. Our data show that statins attenuated the p53 response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil and benzo(a)pyrene. Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 degradation. The induction of p53 responsive genes and apoptosis was attenuated. Mdm2 and p53 were also studied in vivo in rat liver employing immunohistochemistry, and it was found that constitutive Mdm2 expression was changed in livers of pravastatin-treated rats. We also show that the p53 response to a challenging dose of diethylnitrosamine was attenuated in hepatocytes in situ and in primary cultures of hepatocytes by pravastatin pretreatment. Taken together, these data indicate that statins induce an mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the duration and intensity of the p53 response to DNA damage in hepatocytes.

Animals↗
PubMed2001

Statin therapy and stroke prevention.

Hypercholesterolemia has not traditionally been considered an important risk factor in the pathogenesis of stroke. However, recent studies show that statin therapy significantly reduces ischemic stroke for patients with established coronary artery disease. Statin therapy may reduce stroke through amelioration of precerebral atherosclerosis in the carotid artery and the aorta. Anti-atherosclerotic, anti-inflammatory, and antithrombotic actions of statins occur within the blood and in plaque. Statins may also protect against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Ongoing studies are exploring the role of statin therapy in the primary prevention of stroke and in the prevention of cognitive decline and multi-infarct cerebrovascular disease.

Anti-Inflammatory Agents↗
PubMed2003

Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors.

Asymmetric dimethylarginine (ADMA) and monomethylarginine (LMMA) are endogenous inhibitors of nitric oxide synthase. A high level of ADMA in plasma has shown to be a significant risk factor for acute coronary syndromes and elevated plasma ADMA levels are prevalent in patients with hypercholesterolemia. It was therefore hypothesized that lowering plasma cholesterol levels with statin treatment would also lower ADMA concentrations. This double-blind study addressed the effect of high-dose statin treatment on plasma levels of ADMA and LMMA. Forty-eight subjects with mild hypercholesterolemia were randomly assigned to receive simvastatin 80 mg/d, atorvastatin 40 mg/d, or placebo for 8 weeks. Both statins decreased low-density lipoprotein cholesterol effectively (simvastatin 54% and atorvastatin 49%). However, concentrations of arginine derivatives remained unchanged during statin treatment and did not correlate with cholesterol levels. This study indicates that statin treatment has no clear influence on plasma ADMA or LMMA concentrations.

Aged↗
PubMed2002

Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence.

PURPOSE OF REVIEW: Review the cellular mechanisms and clinical evidence for the use of statins in patients with unstable coronary syndromes. RECENT FINDINGS: Clinical trials of statin therapy in acute coronary syndromes demonstrate a rapid improvement in endothelial function, improved perfusion to ischemic myocardium, and an early reduction in cardiovascular events. The early benefit of statin therapy is related to a combination of molecular mechanisms that involve the oxidized LDL receptor (LOX-1), endothelial localized nitric oxide synthase, inflammatory cytokines, interstitial collagenases, and tissue factor expression. In human atheroma, 3 months' use of statin (pravastatin) therapy reduced the content of oxidized LDL, inflammatory cells (macrophage, T cells) infiltrates, and improved plaque stability by increasing the collagen content of the fibrous cap. SUMMARY: The antiatherothrombotic effects of statin therapy appear to have important clinical relevance to patients with impaired myocardial perfusion and acute coronary syndrome.

Acute Disease↗