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At least 595 records · Page 33Linked to original sources
PubMed2006

Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies.

OBJECTIVE: To determine the strength of evidence underlying recommendations for use of statins during the perioperative period to reduce the risk of cardiovascular events. DESIGN: Systematic review of studies with concurrent control groups. DATA SOURCES: Four electronic databases, the references of identified studies, international experts on perioperative medicine, and the authors of the primary studies. Review methods Two reviewers independently extracted data from studies that reported acute coronary syndromes or mortality in patients receiving or not receiving statins during the perioperative period. MAIN OUTCOME MEASURE: Random effects summary odds ratios for death or acute coronary syndrome during the perioperative period. RESULTS: 18 studies--two randomised trials (n=177), 15 cohort studies (n=799,632), and one case-control study (n=480)--assessed whether statins provide perioperative cardiovascular protection; 12 studies enrolled patients undergoing non-cardiac vascular surgery, four enrolled patients undergoing coronary bypass surgery, and two enrolled patients undergoing various surgical procedures. In the randomised trials the summary odds ratio for death or acute coronary syndrome during the perioperative period with statin use was 0.26 (95% confidence interval 0.07 to 0.99) and the summary odds ratio in the cohort studies was 0.70 (0.57 to 0.87). Although the pooled cohort data provided a statistically significant result, statins were not randomly allocated, results in retrospective studies were larger (odds ratio 0.65, 0.50 to 0.84) than those in the prospective cohorts (0.91, 0.65 to 1.27), and dose, duration, and safety of statin use was not reported. CONCLUSION: The evidence base for routine administration of statins to reduce perioperative cardiovascular risk is inadequate.

Case-Control Studies↗
PubMed2003

Evolution of statin prescribing 1994-2001: a case of agism but not of sexism?

OBJECTIVE: To study trends in the use of lipid lowering drugs in the UK, and to assess which patient factors influence prescribing. METHODS: Routinely collected computerised medical data were analysed from 142 general practices across England and Wales that provide data for the Doctors' Independent Network database. Subjects included were people aged 35 years or more with treated ischaemic heart disease, averaging annually over 30,000. The temporal trend from 1994 to 2001 in prescription of lipid lowering drugs and daily statin dose and the odds ratios (ORs) for receiving a statin prescription in 1998 were examined. RESULTS: Lipid lowering drug prescribing increased greatly over time, entirely because of statins, so that in 2001 56.3% of men and 41.1% of women with ischaemic heart disease received lipid lowering drugs. However, 33% of these patients were on a < 20 mg simvastatin daily equivalent. In 1998 the OR for receiving a statin fell from 1 at age 55-64 to 0.64 at 65-74 and 0.16 at 75-84 years. The age effect was similar in those without major comorbidity. Revascularised patients were much more likely to receive a statin than those with angina (OR 3.92, 95% confidence interval (CI) 3.57 to 4.31). Men were more likely to receive a statin than women (OR 1.62, 95% CI 1.54 to 1.71) but this difference disappeared after adjustment for age and severity of disease (OR 1.06). Geographical region had little effect but there was a very weak socioeconomic gradient. CONCLUSIONS: Although prescribing has increased, many patients who may benefit from lipid lowering drugs either do not receive it or are undertreated, possibly because of lack of awareness of the relative potency of the different statins. Patients with angina and the elderly are less likely to receive treatment that may prevent a coronary event.

Adult↗
PubMed2006

American, British and European recommendations for statins in the primary prevention of cardiovascular disease applied to British men studied prospectively.

OBJECTIVE: To compare national and international recommendations for statin treatment in the primary prevention of cardiovascular disease (CVD) in middle-aged men. DESIGN: Application of the current American, British and European recommendations to results of a prospective study. PARTICIPANTS: Men aged 49-65 years (n = 1653) who participated in the Caerphilly Prospective Study. MAIN OUTCOME MEASURES: Proportion of patients who would receive statin treatment, the number needed to treat (NNT) to prevent one first CVD event (myocardial infarction or stroke) over 10 years and the potential number of events prevented over 10 years in the whole population (population impact) by the use of statins in accordance with each set of guidelines, assuming a reduction of risk in the range 10-50% from the observed events and baseline risk factors. RESULTS: 212 events were noted. For an anticipated reduction in first CVD events of 30% with statin treatment, the NNT was 26.0, if the whole population was treated. The lowest NNT was 12.1 for the National Service Framework, achieved when only 14% of the men received a statin. This prevented the lowest number of events (19.2/212), however, and had the smallest population impact on CVD incidence (-9.1%). The American and earlier Joint British Societies guidelines, although giving NNTs of around 21, prevented more events and had a greater population impact of -21.6% to -23.3%. They did, however, target about 60% of the male population. The British Hypertension Society guidelines and new Joint British Societies recommendations achieved the greatest population impact of -27% while maintaining the NNT at 22.2. They did, however, target three quarters of this population. CONCLUSION: Even effective preventive treatment will have little impact in preventing disease if patients at typical risk are not treated. Whether cholesterol lowering on such a scale should be attempted with drugs raises philosophical, psychological and economic considerations, particularly in view of the high likelihood of individual benefit from statin treatment. More effective nutritional policies to reduce serum cholesterol on a population level and reduce the requirement for statins in primary prevention should also be considered.

Aged↗
PubMed1999

Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment.

OBJECTIVES: To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment. DESIGN: Cohort life table method using data from outcome trials. MAIN OUTCOME MEASURES: The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from pound 100 to pound 800 per year. RESULTS: The costs per life year gained according to annual CHD event risk were: for 4.5%, pound 5100; 3.0%, pound 8200; 2.0%, pound 10 700; and 1.5%, pound 12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks. CONCLUSIONS: At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.

Coronary Disease↗
PubMed2006

Statin therapy at carotid angioplasty and stent placement: effect on procedure-related stroke, myocardial infarction, and death.

PURPOSE: To retrospectively determine if preprocedural statin treatment is associated with a reduction of cardiovascular events after carotid angioplasty and stent placement (CAS) in patients with symptomatic carotid stenosis. MATERIALS AND METHODS: A study resulting in a prospective database was approved by the institutional ethics review board; written informed consent was obtained. The approval and informed consent included future retrospective analysis. Consecutive patients (n = 180) from the prospective database underwent CAS for high-grade symptomatic carotid disease. The frequency of cardiovascular complications (composite of stroke, myocardial infarction, and death within 30 days after CAS) between 127 patients without preprocedural statin treatment and that of 53 patients with preprocedural statin treatment at CAS were compared with chi2 and multivariate logistic regression analysis. RESULTS: The overall 30-day myocardial infarction rate was two of 180 (1%) patients, the minor stroke rate was 16 of 180 (9%) patients, the major stroke rate was one of 180 (0.5%) patients, and the death rate was two of 180 (1%) patients. The incidence of cardiovascular events (composite of stroke, myocardial infarction, and death within 30 days after CAS) was significantly different between patients with preprocedural treatment (4%) and those without preprocedural statin treatment (15%) (P < .05). These higher complication rates among patients without preprocedural statin treatment were not mediated by adjustment for age, sex, other baseline characteristics, degree of carotid stenosis, use of cerebral protection devices, or the year in which CAS was performed. CONCLUSION: Preprocedural statin therapy appears to reduce the incidence of stroke, myocardial infarction, and death within 30 days after CAS. Future prospective randomized trials are warranted to further assess this potential protective effect of statin drugs during carotid interventions.

Aged↗
PubMed2006

Statin use and risk of lymphoid neoplasms: results from the European Case-Control Study EPILYMPH.

BACKGROUND: Statins, drugs used to treat dyslipidemia, may have anticancer properties. We have evaluated lymphoma risk associated with regular statin use in an international case-control study. METHODS: This case-control study included 2,362 cases of incident B- and T-cell lymphoma from Czech Republic, France, Germany, Ireland, Italy, and Spain and 2,206 hospital or population controls. Information on drug use, diagnosis at admission (for hospital controls), and putative risk factors for lymphoma was collected with personal interviews. Hospital controls admitted for diseases possibly entailing use of statins were excluded from the analysis. RESULTS: The odds ratio for regular statin use was 0.61 (95% confidence interval, 0.45-0.84); all major lymphoma subtypes showed similarly decreased risks. Decreased risks were observed in all centers. Duration of statin use was not associated with a greater reduction in the risk of lymphoma. Use of other lipid lowering drugs, such as fibrates, did not significantly modify the risk of lymphoma (odds ratio, 0.75; 95% confidence interval, 0.44-1.27). CONCLUSION: Statin use was associated with an important reduction in lymphoma risk, adding to the growing evidence of anticancer properties of this group of drugs. These results are reassuring for the increasing number of patients taking statins on a regular basis.

Adult↗
PubMed2006

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs.

Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin- and cytostatic drug-induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR-dependent manner. Statins also induced mTOR-dependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53.

Antineoplastic Agents↗
PubMed2004

Statins and stroke prevention.

Four randomized trials with a statin and one trial with a fibrate showed a modest but significant absolute reduction in the incidence of stroke in patients with a previous myocardial infarction. The reasons for the positive effect of statins on stroke end-point are unclear since, paradoxically, the link between serum cholesterol level and stroke has never been fully established. Furthermore, the positive results of statins trials were mainly obtained in patients with an average or a low serum cholesterol level. This suggests nonhypolipidemic effects of these drugs, so-called pleiotropic effects, acting on the biologic promoters of plaque instability. Statins have a good overall safety profile with no increase of hemorrhagic stroke and no increase in cancer. They have positive effects in primary prevention of cardiovascular disease in high-risk young as well as elderly populations. Statins reduced stroke incidence in high-risk (mainly CHD, diabetics and hypertensives) population even with a normal baseline blood cholesterol level, which argues for a global cardiovascular risk-based treatment strategy. In patients with prior strokes, statins likely reduce the incidence of cononary events, but it is not yet proven that statins actually reduce the incidence of recurrent strokes in secondary prevention. If current hypotheses are verified by ongoing trials, we may expect between 20 to 30 more stroke events avoided per 1,000 patients treated during 2 years with a lipid-lowering agent, which adds to the 28 stroke events prevented with an antiplatelet agent over the same time period. This would be one of the most significant advances in stroke and vascular dementia prevention since the era of aspirin therapy.

Cholinergic Antagonists↗
PubMed2006

Statin use before by-pass surgery decreases the incidence and shortens the duration of postoperative atrial fibrillation.

BACKGROUND: The aim of the present observational study is to search the incidence of postoperative atrial fibrillation (AF) in patients with or without preoperative statin treatment. METHODS AND RESULTS: The population consisted of 362 consecutive patients (267 on and 95 not on statin). Diabetes mellitus was more frequent in statin group (p = 0.03). Other demographic and procedural variables were similar in the both groups (All p > 0.05). Postoperative AF was less frequent and its duration was shorter in statin group compared to non-statin group (p = 0.03 and 0.0001, respectively). The Kaplan-Meier analysis showed the protective effect of statins against the risk of developing AF (p = 0.01). CONCLUSION: Statin treatment before the by-pass surgery decreases the incidence and shortens the duration of postoperative AF.

Aged↗
PubMed2006

Inhibitory effect of statins on renal epithelial-to-mesenchymal transition.

BACKGROUND/AIM: Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal tubular cells' epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1. METHODS: Human proximal tubular epithelial cells (HK2) were used to examine the inhibitory effect of statins on EMT induced with medium conditioned by activated peripheral blood mononuclear cells. RESULTS: Our study demonstrates that the statins lovastatin, simvastatin, and pravastatin inhibit HK2 cells to undergo EMT. Inhibition of EMT in HK2 cells with these statins resulted in a reduction of RhoA and Rac1 activation in both the cytoplasmic and membrane-bound forms, in preservation of the expression of the epithelial cell markers E-cadherin and cytokeratin-19, and in a decrease in Fn-EDA expression, a marker for the myofibroblast phenotype. The decreased levels of activated RhoA and Rac1 in both the cytoplasmic and membrane fractions of the cells were reversed by geranylgeranyl pyrophosphate and mevalonate, and thus attributable to the inhibition of isoprenylation of RhoGTPases by statins. CONCLUSION: This phenomenon could explain the beneficial effect of statins on EMT and on renal fibrosis prevention.

Cell Differentiation↗
PubMed2003

Statins as novel immunomodulators: from cell to potential clinical benefit.

In the last decades, substantial progress has been made in understanding the relationship between lipid disorders and prevention of cardiac ischemic disease. Statins competitively inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol biosynthesis. Statins have long been thought to exert their benefits by reducing cholesterol synthesis, but the fact that mevalonate is the precursor of isoprenoids that regulate diverse cellular functions has led investigators to examine pleiotropic effects for these agents. Statins have never been shown to be involved in the immune response, although two clinical trials have suggested that in heart transplant patients, statin therapy has beneficial effects on the incidence of cardiac rejection, coronary vasculopathy, and survival. Major Histocompatibility Complex class II (MHC-II) molecules, which affect the immune response and organ rejection after transplantation, may be induced by the pro-inflammatory cytokine interferon gamma (IFN-gamma). Recently, it has been demonstrated that statins repress the induction of MHC-II by IFN-gamma in vitro, and thus may suggest a potential role for statins as immunosuppressive agents in vivo. Indeed, two recent in vivo studies performed on different animal models provide further evidence that statin-treatment positively influence immunological disorders.

Adjuvants, Immunologic↗
PubMed2003

Statins inhibit secretion of metalloproteinases-1, -2, -3, and -9 from vascular smooth muscle cells and macrophages.

OBJECTIVE: Production of several metalloproteinases (MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages. METHODS AND RESULTS: We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, -3, and -9 secretion from human SMC by 52+/-19%, 71+/-18%, and 73+/-17%, respectively (P<0.01, n=3). Similar dose-related effects of cerivastatin (50 to 500 nmol/L), simvastatin (1 to 20 micromol/L), and lovastatin (5 to 20 micromol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, -3, and -9 and constitutive MMP-2 secretion but not TIMP-1 or -2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, -3, and -9 secretion from rabbit foam cells; cerivastatin (50 nmol/L) inhibited by 68+/-18%, 74+/-14%, and 74+/-14%, respectively (P<0.01, n=4). Statins similarly decreased collagenolytic, caseinolytic, and gelatinolytic activity. Mevalonate and geranylgeranylpyrophosphate but not squalene reversed the effects, showing dependence on isoprenoid, not cholesterol depletion. Statins did not affect MMP mRNA levels. CONCLUSIONS: Statins inhibit secretion of a several MMPs from both SMCs and macrophages, which could therefore contribute to their plaque-stabilizing effects.

Animals↗
PubMed2004

Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.

OBJECTIVES: We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro. METHODS AND RESULTS: Cultured porcine AVMFs and M2-10B4 cells were treated with simvastatin and pravastatin. Mevalonate, a 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase metabolite, was added in parallel experiments. Manumycin A, which inhibits protein prenylation, was added to cultures in the absence of statins. Calcification was assessed by counting the number of calcific nodules formed and measuring alkaline phosphatase activity (APA). Statins inhibited calcific nodule formation (P<0.01) and APA (P<0.01) in AVMFs. Mevalonate reversed the statin effect on nodule formation (P<0.05) and APA (P<0.01). Manumycin A had no effect on either parameter. M2-10B4 cells treated with simvastatin formed more calcific nodules compared with controls (P<0.01), although pravastatin had no effect. Both statins, however, resulted in increased APA in M2-10B4 cells (P<0.01). Mevalonate had no impact on nodule numbers or APA in M2-10B4 cells. CONCLUSIONS: Statins inhibit calcification in AVMFs by inhibiting the cholesterol biosynthetic pathway, independent of protein prenylation, but paradoxically stimulate bone cell calcification. Because 15% of patients with end-stage valvular heart disease exhibit mature bone in their aortic valves, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.

Animals↗
PubMed2003

Statins promote potent systemic antioxidant effects through specific inflammatory pathways.

BACKGROUND: The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. METHODS AND RESULTS: As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. CONCLUSIONS: Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Antioxidants↗
PubMed2004

Beyond the laboratory: clinical implications for statin pleiotropy.

Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density-lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.

Arteriosclerosis↗
PubMed1998

Cholesterol reduction yields clinical benefit: impact of statin trials.

BACKGROUND: We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. METHODS AND RESULTS: We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. CONCLUSIONS: Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

Cholesterol↗
PubMed2002

Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury.

Complement-mediated vascular injury is important in the pathophysiology of atherosclerosis and myocardial infarction. Because recent evidence shows that statins have beneficial effects on endothelial cell (EC) function independent of lipid lowering, we explored the hypothesis that statins modulate vascular EC resistance to complement through the upregulation of complement-inhibitory proteins. Human umbilical vein and aortic ECs were treated with atorvastatin or simvastatin, and decay-accelerating factor (DAF), membrane cofactor protein, and CD59 expression was measured by flow cytometry. A dose-dependent increase in DAF expression of up to 4-fold was seen 24 to 48 hours after treatment. Statin-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. L-Mevalonate and geranylgeranyl pyrophosphate reversed the effect, confirming the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and suggesting that constitutive DAF expression is negatively regulated by geranylgeranylation. Neither farnesyl pyrophosphate nor squalene inhibited statin-induced DAF expression, suggesting that the effect is independent of cholesterol lowering. Statin-induced DAF upregulation was mediated by the activation of protein kinase Calpha and inhibition of RhoA and was independent of phosphatidylinositol-3 kinase and NO activity. The increased DAF expression was functionally effective, resulting in significant reduction of C3 deposition and complement-mediated lysis of antibody-coated ECs. These observations provide evidence for a novel cytoprotective action of statins on vascular endothelium that is independent of the effect on lipids and results in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression may contribute to the early beneficial effects of statins in reducing the morbidity and mortality associated with atherosclerosis.

Atorvastatin↗
PubMed2005

Rho GTPases, statins, and nitric oxide.

The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are used in the prevention and treatment of cardiovascular diseases. Recent experimental and clinical studies suggest that statins may exert vascular protective effects beyond cholesterol reduction. For example, statins improve endothelial function by cholesterol-dependent and -independent mechanisms. The cholesterol-independent or "pleiotropic" effects of statins include the upregulation and activation of endothelial NO synthase (eNOS). Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important posttranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. Indeed, decrease in Rho GTPase responses as a consequence of statin treatment increases the production and bioavailability of endothelium-derived NO. The mechanism involves, in part, Rho/Rho-kinase (ROCK)-mediated changes in the actin cytoskeleton, which leads to decreases in eNOS mRNA stability. The regulation of eNOS by Rho GTPases, therefore, may be an important mechanism underlying the cardiovascular protective effect of statins.

Actins↗