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PubMed2004

Statin myotoxicity is associated with changes in the cardiopulmonary function.

The mechanism of the muscle toxicity associated with lipid-lowering therapy remains obscure. Pathological and biochemical findings in patients with statin myotoxicity suggest impaired fatty acid oxidation. Exhaled gas analysis can be used to assess substrate utilization including fatty acid oxidation. In order to determine if muscle toxicity due to lipid-lowering therapy might be related to abnormalities in lipid oxidation, exhaled gas analysis was performed in the fasted state on 11 patients subsequent to statin-associated myositis reactions. Results were compared to those of 16 normal controls who were measured both on and off statin therapy. Post-myositis patients showed a depressed anaerobic threshold (AT) (P=0.009) compared to controls while age-adjusted maximal oxygen consumption (VO2max) and ventilatory efficiency (VE/VCO2) were not significantly different. The fasting respiratory exchange ratio (RER) of post-myositis patients off statins was abnormally increased (P=0.00001) as was their S1-slope (P=0.023). Controls demonstrated a significant increase in their RER while taking statins consistent with decreased lipid oxidation (P <0.00001). These findings suggest that abnormal lipid oxidation in certain patients may predispose them to the myotoxicity caused by lipid-lowering therapies.

Aged↗
PubMed2005

Visualizing coronary calcium is associated with improvements in adherence to statin therapy.

BACKGROUND: Many patients lack motivation to control cardiovascular risk factors and clinicians have long sought ways to activate apathetic patients. Despite significant and consistent data on the benefits of lipid-lowering agents to reduce cardiovascular events, adherence and utilization of these agents remains low. We evaluated whether visualization of coronary calcium would positively affect patients' adherence rates. METHODS: We evaluated patients who underwent electron beam tomography (EBT) coronary calcium evaluation at least 1 year prior with a survey questioning them about health behaviors. Patients filled out baseline and follow-up questionnaires relating to lifestyle modifications, including statin utilization, diet, exercise, tobacco cessation and vitamin/antioxidant utilization. RESULTS: The study population consisted of 505 individuals on statin therapy on baseline who were followed for a mean of 3 +/- 2 years. Overall the statin compliance was lowest (44%) among those with CAC score in the first quartile (0-30), whereas 91% of individuals with baseline CAC score in the fourth quartile (>or= 526) adhered to statin therapy. In multivariable analysis, after adjusting for cardiovascular risk factors, age, and gender, higher baseline CAC scores were strongly associated with adherence to statin therapy. CONCLUSIONS: In addition to risk stratification for the asymptomatic person, patients visualizing coronary artery calcium may improve utilization and adherence to lipid-lowering therapy. Outcome studies and randomized trials need to be done to quantify the true value and cost-effectiveness of this approach.

Calcinosis↗
PubMed2006

Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation.

To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.

Adult↗
PubMed2006

Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization.

OBJECTIVE: The transcription factor KLF2 is considered an important mediator of the anti-inflammatory and anti-thrombotic properties of the endothelium. KLF2 is absent from low-shear, atherosclerosis-prone sites of the vascular tree but is induced by HMG-CoA reductase inhibitors (statins) in vitro. We studied KLF2-dependent induction of important determinants of the atheroprotective status of the endothelium to determine whether pharmacological intervention, e.g. by statins, can potentially replace shear stress. METHODS: Shear stress and statin effects in combination with TNF-alpha were determined in human umbilical vein endothelial cells by quantitative measurements of the steady-state levels and stability of mRNA for KLF2 and its downstream target genes thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS). RESULTS: We demonstrate that prolonged shear stress has a potential that is superior to that of statins to induce the KLF2-dependent expression of eNOS and TM, especially in the presence of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). These effects can be attributed to the sustained stabilization of KLF2 mRNA by shear, leading to an increased KLF2 protein expression and concomitant strong induction of KLF2 downstream targets. The stabilization of KLF2 mRNA is demonstrated to be dependent on signaling involving phosphoinositide 3-kinase (PI3K). CONCLUSION: The stabilization of KLF2 steady-state levels, as induced by prolonged shear stress but not by statins, may be essential for sustaining the quiescent, atheroprotective status of the vascular endothelium under inflammatory conditions.

Atherosclerosis↗
PubMed2005

Changes of plasma inflammatory markers after withdrawal of statin therapy in patients with hyperlipidemia.

BACKGROUND: Atherosclerosis has been considered to be an inflammatory process. In addition to its lipid-lowering properties, statin has been shown to decrease the concentrations of inflammatory markers resulting in reduction of cardiovascular events. Emerging data suggest that withdrawal of statin might be associated with increased cardiac events. The mechanism for this phenomenon, however, is still unclear. We investigated whether acute termination of statin treatment could result in rebound of inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), in patients with hyperlipidemia. METHODS: Seventeen patients (11 men and 6 women, mean age 51+/-7 years) with hyperlipidemia were given 40 mg/day of pravastatin for 6 weeks. The concentrations of plasma CRP and IL-6 were evaluated before receiving the statin therapy, immediately after 6 weeks of pravastatin therapy, and at days 1, 3 and 7 after withdrawal of pravastatin therapy. The lipid profile was also evaluated at baseline, 6 weeks of therapy, and at day 7 after terminating pravastatin. RESULTS: Pravastatin therapy induced significant reductions in total cholesterol (TC, 6.88+/-0.36 vs. 5.27+/-0.23 mmol/l, p<0.01), low-density lipoprotein (LDL) cholesterol (4.28+/-0.25 vs. 3.06+/-0.14 mmol/l, p<0.01), CRP (0.28+/-0.16 vs. 0.20+/-0.08 mg/l, p<0.01), and IL-6 (8.4+/-0.6 vs. 6.7+/-0.4 pg/dl, p<0.01). Although the TC and LDL-cholesterol did not change during the 7-day period after withdrawal of pravastatin therapy, the concentrations of CRP and IL-6 increased at day 3 (CRP: 0.20+/-0.08 vs. 0.27+/-0.12 mg/l, and IL-6: 6.7+/-0.4 vs. 7.7+/-0.6 pg/dl, p<0.05 respectively) and at day 7 (CRP: 0.20+/-0.08 vs. 0.30+/-0.14 mg/l, and IL-6: 6.7+/-0.4 vs. 8.7+/-0.8 pg/dl, p<0.01 respectively) after withdrawal of pravastatin therapy. No correlation between increase of CRP as well as IL-6 and small changes of LDL-cholesterol concentrations was found after withdrawal of pravastatin therapy at day 7 (r=-0.021 and r=-0.044 respectively, p>0.05 respectively). CONCLUSIONS: 6 weeks after pravastatin therapy could significant modify the lipid profile and decrease the inflammatory markers including CRP and IL-6 in patients with hyperlididemia. Moreover, statin therapy discontinuation could induce a rebound phenomenon of inflammatory response representing an increase in some inflammatory markers, which is independent of changes of lipid parameters.

Adult↗
PubMed2005

Non-cholesterol sterols in serum, lipoproteins, and red cells in statin-treated FH subjects off and on plant stanol and sterol ester spreads.

BACKGROUND: Serum plant sterol levels are increased by consumption of statins and dietary plant sterols, and decreased by dietary plant stanols, but little is known about combination therapy of statin and plant sterols. METHODS: We measured plant sterols in serum, lipoproteins, and red cells in subjects with familial hypercholesterolemia (FH) (n=18) treated with variable doses of statins off and on plant stanol (STA) and sterol ester (STE) spreads. RESULTS: STA and STE spreads lowered LDL cholesterol approximately 15%. Plant sterols were decreased in serum, lipoproteins, and red cells by approximately 25% with STA and increased from 37% to 80% with STE, especially with high statin doses. The changes in serum were related to those in red cells. The baseline levels of serum plant sterols were negatively (r-range -0.639 to -0.935) and positively (r-range 0.526 to 0.598) correlated with the respective changes evoked by the STA and STE spreads. CONCLUSIONS: STE reduces LDL cholesterol, but increases serum, lipoprotein, and red cell plant sterol levels in statin-treated FH subjects, while all the respective values are decreased with STA. Recent predictions that elevated serum plant sterols pose an increased coronary risk suggest that increases of serum plant sterol levels should be avoided, especially in atherosclerosis-prone individuals, such as subjects with FH.

Adult↗
PubMed2005

Compliance with a statin treatment in a usual-care setting: retrospective database analysis over 3 years after treatment initiation in health maintenance organization enrollees with dyslipidemia.

BACKGROUND: Patients treated in a usual-care setting often do not comply with prescribed treatment regimens as closely as those treated in a clinical trial, for a variety of reasons. OBJECTIVES: We sought to describe compliance over 3 years with a statin treatment in an observational study in a usual-care setting and to investigate potential risk factors for poor compliance. METHODS: Enrollees in a Massachusetts health maintenance organization (HMO) who presented with baseline low-density lipoprotein cholesterol (LDL-C) > or =130 mg/dL and who started statin treatment between January 1, 1994, and July 1, 1999, were followed until death, termination of membership in the HMO, or July 1, 1999, whichever came first, as documented by the HMO's drug-dispensing electronic records. The records included information about the demographics, service dates, laboratory data, and filled prescriptions. The outcome measures were time to treatment discontinuation, time to treatment resumption, and adherence to treatment. RESULTS: A total of 4776 enrollees were included in the analysis. Most patients were aged 50 to 69 years (57%), men (52%), had LDL-C > or =160 mg/dL (77%), and received their prescription for antihyperlipidemia therapy from an internist or family physician (87%). The hazard of discontinuation was high during the first 6 months of therapy, with 20% of the initial population discontinuing treatment during this time period, then decreased, so that the fraction of continuing users leveled off: 74%, 65%, and 61% of statin initiators were still on treatment 1, 2, and 3 years after entry, respectively. The probability of resuming statin treatment was 51% within 24 months after last prescription filled. The proportion of adherent users stayed stable, between 53% and 55%, after the first 6 months. Risk factors of treatment discontinuation, treatment resumption, and adherence were remarkably similar and were stable over time. The significant predictors of treatment discontinuation were age <50 years (hazard ratio [HR], 1.45 [95% Cl, 1.26-1.68]), female sex (HR, 1.18 [95% CI, 1.06-1.30], and previous antihyperlipidemia treatment (HR, 0.71 [95% CI, 0.63-0.79]). CONCLUSIONS: In this HMO setting, women and individuals 1026 aged <50 years were at risk for poor compliance with statin therapy. Our analysis suggests that the association between compliance and age or gender may be quite stable over the first 3 years of treatment.

Age Factors↗
PubMed2005

High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.

BACKGROUND: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle. METHODS: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up. RESULTS: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin. CONCLUSIONS: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Adult↗
PubMed2006

An overview of statin-associated proteinuria.

Statins are an established therapeutic modality for the treatment of hypercholesterolemia. Although they generally exhibit a good efficacy and tolerability profile, their reputation has been tarnished as a result of reports of myotoxicity and, more recently, observations of proteinuria. The increased incidence of proteinuria with rosuvastatin was of particular concern, and raised questions about the renoprotective actions of statins. Different hypotheses have been put forward to explain the mechanisms of statin-induced proteinuria. The multifarious effects of statins, independent of their effects on cholesterol-lowering, form the basis of such hypotheses. However, rosuvastatin-associated proteinuria is transient and reversible and even at the highest dose did not affect renal function after prolonged treatment. It would appear that clinically relevant proteinuria is not associated solely with rosuvastatin and might represent a minor class effect of statins with a fairly low incidence. However, definitive proof of this assertion will need to be provided by rigorous testing.

Animals↗
PubMed2004

The role of statins in vascular disease.

BACKGROUND: Recent publications have highlighted the benefits of statins in non-cardiac occlusive disease but also the failure of vascular surgeons to recognise and treat the risk factors for atherosclerosis, in particular hypercholesterolaemia. The aim of this review is to clarify the current experimental and clinical evidence for the use of statins in vascular disease. METHODS: Literature compiled from an extensive search of Medline and the Cochrane database has been used for the basis of this review. RESULTS: Experimental and clinical evidence consistently reports that statins improve endothelial dysfunction, are anti-inflammatory, anti-proliferative, anti-thrombogenic and anti-proteolytic. These effects are known to inhibit atherogenesis and improve plaque stability. Independent groups support the use of statins in the prevention of both primary and secondary cardiac events. The National Stroke association recommends their use to reduce strokes following myocardial infarction and the Heart Protection Study reports benefits in patients with non-cardiac occlusive disease. CONCLUSIONS: There is substantial evidence advocating the use of statins in patients with clinically significant vascular disease. In the future this may evolve to include those patients at risk from neointimal hyperplasia, aneurysmal disease and ischaemia reperfusion injury.

Cardiovascular Diseases↗
PubMed2006

Statins are associated with a reduced infrarenal abdominal aortic aneurysm growth.

OBJECTIVE: To evaluate the effect of statins on aneurysm growth in a group of consecutive patients under surveillance for infrarenal aortic aneurysms (AAA). MATERIALS AND METHODS: All patients (59 statin users, 91 non-users) under surveillance between January 2002 and August 2005 with a follow-up for aneurysm growth of at least 12 months and a minimum of three diameter evaluations were retrospectively included in the analysis. Multiple regression analysis, weighted with the number of observations, was performed to test the influence of statins on AAA growth rate. RESULTS: During a median period of 3.1 (1.1-13.1) years the overall mean aneurysm growth rate was 2.95+/-2.8 mm/year. Statin users had a 1.16 mm/year lower AAA growth rate compared to non-users (95% CI 0.33-1.99 mm/year). Increased age was associated with a slower growth (-0.09 mm/year per year, p = 0.003). Female gender (+1.82 mm/year, p = 0.008) and aneurysm diameter (+0.06 mm/year per mm, p = 0.049) were associated with increased AAA growth. The use of non-steroidal anti-inflammatory drugs, chronic lung disease, or other cardiovascular risk factors were not independently associated with AAA growth. CONCLUSIONS: Statins appear to be associated with attenuation of AAA growth, irrespective of other known factors influencing aneurysm growth.

Aged↗
PubMed2006

Lectin-like oxidized-LDL receptor-1 (LOX-1) polymorphisms influence cardiovascular events rate during statin treatment.

BACKGROUND: Oxidized-LDL (ox-LDL) are involved in atherothrombosis by induction of endothelial dysfunction and thrombosis. The specific receptor lectin-like oxidized-LDL receptor-1 (LOX-1) is expressed in endothelial cells, monocytes and platelets. LOX-1 gene allelic variants (3'UTR/T) have been related with cardiovascular events and reduced anti-platelet activity induced by statins. OBJECTIVES: To detect whether LOX-1 polymorphisms could affect statins effectiveness in cardiovascular prevention. PATIENTS/METHODS: The present was a retrospective study performed in 751 white hypercholesterolemic subjects treated with increasing doses of atorvastatin (n=382, 247 male, 135 female) or simvastatin (n=369, 244 male, 125 female) up to 4 years, whose LDL target was 3.36 mmol/L according to the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATPIII). Single nucleotide polymorphism were evaluated by allelic discrimination assays (PCR), lipid profile by enzymatic-colorimetric methods and C-reactive protein (CRP) by a nephelometric technique. RESULTS: Twenty-three non-ST elevation (NSTEMI) and eleven ST-elevation myocardial infarction (STEMI) were encountered in the observational period without differences between treatments (p=0.175) and sex (p=0.139). Each symptomatic subject (10 reaching the appropriate LDL target and 24 with still undesirable LDL) had the 3'UTR/T allelic variant (adjusted O.R. 4.63, 95% C.I. 3.46-6.70, p<0.0001). Among patients not reaching LDL target the C allele resulted protective with respect to T carriers (p<0.00001). Also, similar changes of CRP resulted in different event rate between T and C carriers (p<0.001) in the whole cohort. CONCLUSIONS: In the studied population LOX-1 genetic variants influence cardiovascular risk reduction induced by statins also in patients not reaching the LDL target. The previously described LOX-1-related antithrombotic actions of both statins employed could have a specific role in what observed, suggesting a genetic influence in statins LDL-lowering partially related actions.

Aged↗
PubMed2006

Immunomodulatory effects of statins and autoimmune rheumatic diseases: novel intracellular mechanism involved.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are the most commonly prescribed agents for the treatment of hypercholesterolemia. However, the effects of statins may extend beyond their influences on serum cholesterol levels resulting in cholesterol-independent or pleiotropic effects. Clinical, animal and in vitro studies suggest that statins have additional clinical uses because of their anti-inflammatory and immunomodulatory effects, in part due to their capacity to interfere with the mevalonate pathway and inhibit prenylation of Rho family GTPases. This review focuses on the molecular mechanisms of the anti-inflammatory and immunomodulatory effects of statins. In base to all these information, we suggest that statins could have similar inhibitory effects on MAPKs pathways in cells from RA patients, including osteoclasts and fibroblasts.

Animals↗
PubMed2007

Statins and the vascular endothelial inflammatory response.

Statins reduce cholesterol synthesis and are widely used for the treatment of hyperlipidaemia and ischaemic heart disease. Besides their cholesterol-lowering effects, statins also possess broad immunomodulatory and anti-inflammatory properties. Vascular endothelial cells have a crucial role in the pathogenesis of inflammatory disease, and, alongside leukocytes and antigen-presenting cells, represent a key cellular target for statin therapy. Recent studies investigating how these drugs modify endothelial cell function demonstrate that the therapeutic effect of statins can be attributed, in part, to their action on the endothelium. Accordingly, statins attenuate endothelial MHC class II expression, increase endothelial nitric oxide synthase and fibrinolytic activity, decrease leukocyte adhesion and transmigration, and enhance resistance to local injurious stimuli. Many of these effects are brought about by the modulation of small GTPase function and the downregulation of proinflammatory gene expression.

Animals↗
PubMed2004

Lipid lowering effects of statins and fibrates in the management of HIV dyslipidemias associated with antiretroviral therapy in HIV clinical practice.

OBJECTIVES: Dyslipidemia associated with antiretroviral therapy is a common clinical problem among HIV-infected patients. Considering that the challenge of adherence to drugs (both antiretroviral and lipid lowering) may be substantial in routine HIV care, our objective was to evaluate the lipid-lowering effects of statins and fibrates in the management of HIV dyslipidemias in clinical practice setting. METHODS: Retrospective review of 103 ethnically diverse dyslipidemic HIV patients on antiretroviral therapy treated with lipid-lowering drugs (using National Cholesterol Education and Prevention II [NCEP II] guidelines) who were followed for a median of 70 weeks. RESULTS: An overall mean reduction of 16% in total cholesterol, 20% non-HDL cholesterol, and 18% in triglycerides was noted. There were no significant changes in HDL levels. On evaluation of the different drug classes, the mean (median) change in total cholesterol, were -9 (-7)% with fibrates, -11 (-14)% with statins and -23 (-22)% for dual therapy with fibrates and statins. The triglycerides decreased by -11 (-40)% in those treated with fibrates; -1 (-21)% in those with statins alone, and -32 (-42)% in those with dual therapy. Overall less than a fifth of patients reached the defined NCEP target goal reduction. On logistic regression analysis, only stopping protease inhibitors/ritonavir was independently associated with significant cholesterol reduction (OR: 10.14; 95% CI: 2.1-48.9; p < 0.005). CONCLUSION: In a primary care setting, the use of statins and/or fibrates may add to the complexity of HIV care, with only modest lipid lowering effects.

Adult↗
PubMed2006

Statins in the treatment of central nervous system autoimmune disease.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are widely prescribed for their cholesterol-lowering properties to reduce atherogenesis and cardiovascular morbidity. Over recent years, statins have also been shown to exert pleiotropic immunomodulatory effects that might be of therapeutic benefit in autoimmune disorders. The primary mechanism by which statins alter immune function appears to be mediated through the inhibition of post-translational protein prenylation of small GTP-binding proteins and is largely independent of lipid-lowering. In experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), statins prevent or reverse paralysis and were recently shown to exert synergistic benefit when combined with agents approved for MS therapy. Based primarily upon the beneficial effects in EAE, statins are now being tested in patients in MS clinical trials.

Animals↗
PubMed2005

Putative mechanisms of action of statins in multiple sclerosis--comparison to interferon-beta and glatiramer acetate.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-beta. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-beta and glatiramer acetate (GA).

Adjuvants, Immunologic↗
PubMed2004

Statins potentiate caspase-3 activity in immortalized murine neurons.

Statins are lipid-lowering drugs that have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. However, there is growing evidence from epidemiological studies that long-term treatment with statins has unwanted effects on extrahepatic tissue and increases the risk for neuropathy. To investigate underlying molecular mechanisms we analyzed whether statins influence the activity of caspase-3 in immortalized neurons. Lovastatin and mevastatin are not able to activate caspase-3 but they strongly potentiate its activity when apoptotic signal transduction is initiated by staurosporine. The increase in caspase-3 activity after coincubation with statins and staurosporine was paralleled by an increase in the protein level of the pro-apoptotic GTPase RhoB. Our data provide evidence that statins enhance neuronal apoptosis and therefore give reasons for a careful evaluation when patients with neurological diseases are treated with these drugs.

Animals↗