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PubMed2006

Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.

We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

Adult↗
PubMed2004

Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling.

Cell migration is a key event in repair and remodeling of skeletal tissues, but the mechanism of osteoblast migration has not been resolved. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, increase bone. However, the effect of statins on osteoblast migration remains to be clarified. We investigated the effect of fluvastatin and mevastatin on platelet-derived growth factor (PDGF)-induced migration of osteoblastic MC3T3-E1 cells. PDGF promoted osteoblast migration, while the statins inhibited PDGF-induced migration, and mevalonate and geranylgeranylpyrophosphate but not farnesylpyrophosphate abolished the effect of statins. Dominant-negative Rac severely inhibited PDGF-induced osteoblast migration and reduced Akt phosphorylation. Further, fluvastatin reduced Akt phosphorylation and dominant-negative Akt inhibited PDGF-induced osteoblast migration. These results demonstrate that statins inhibit PDGF-induced osteoblast migration and Rac-Akt signaling plays an important role in the osteoblast migration, and suggest that statins restrain Rac function by inhibiting geranylgeranylation of Rac, which leads to the reduction in Akt activation and osteoblast migration.

Animals↗
PubMed2005

Statins downregulate myeloperoxidase gene expression in macrophages.

Statins, inhibitors of HMG-CoA reductase, have pleiotropic benefits independent of cholesterol levels, including anti-oxidant and anti-inflammatory effects. Here, we investigate the effect of statins on myeloperoxidase (MPO) expression. MPO, expressed in foam cell macrophages, was recently shown to oxidize the ApoA-1 component of HDL, impairing ABCA-1 mediated cholesterol efflux. High levels of serum MPO correlate with increased risk of CAD events. Findings here show that statins strongly inhibit MPO mRNA expression in human and murine monocyte-macrophages. Suppression was reversed by downstream intermediates of HMG-CoA reductase, mevalonate, and geranylgeranylpyrophosphate, but not farnesylpyrophosphate. An inhibitor of geranylgeranyltransferase, GGTI-286, mimics the effects of statins, indicating geranylgeranylation is key to MPO expression. Reduction of MPO mRNA levels was observed in vivo in leukocytes from statin-fed mice, correlating with reductions in MPO protein and enzyme activity. These findings suggest that the pleiotropic protections afforded by statins may be due in part to suppression of MPO expression.

Alleles↗
PubMed2006

Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo.

Heme oxygenase-1 (HO-1) plays a central role in antioxidant and anti-inflammatory actions, which may be mediated through its formation of biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors (statins) induce in vitro HO-1 expression and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature. We characterized the effects of statins on in vivo HO-1 expression in various extravascular tissues: liver, lung, brain, and heart. Adult mice were orally administered simvastatin, lovastatin, atorvastatin, or rosuvastatin. HO activity significantly increased in a statin- and tissue-specific manner, with all statins increasing heart and lung activity within 24 h. Significant elevations of HO-1 protein and mRNA were also observed in heart and lung after atorvastatin treatment. We conclude that in vivo HO-1 induction is statin- and tissue-specific. Through this pathway, statins may confer antioxidant and anti-inflammatory actions in the vasculature and extravascular systems.

Animals↗
PubMed2006

Statins associated with reduced mortality in patients admitted for congestive heart failure.

BACKGROUND: Statins may be of potential benefit in patients with congestive heart failure (CHF) due to modulation of neurohormones and their antioxidant, antiinflammatory, and antifibrotic properties. To test this hypothesis, we performed a case-control study by using a prospective registry of patients admitted to our hospital for CHF. METHODS AND RESULTS: The Maastricht Registry of Congestive Heart Failure consists of a cohort of all patients who were admitted to the University Hospital Maastricht because of CHF for the first time between 1998 and 2000. Elective admissions were not included in the database. Drug treatment was left at the discretion of the attending physician. From a total of 840 patients admitted, we selected patients with an uncomplicated survival for at least 1 month after hospital discharge. For each survivor a nonsurvivor was matched for age, sex, left ventricular ejection fraction, and renal function. Drugs were considered in use only if they were administered for at least 90% of follow-up time. Five hundred twenty-four patients were included with a mean follow-up after discharge of 31 +/- 18 months. Twenty percent used statins. In Cox multivariate regression analysis, the use of statins remained significantly associated with decreased mortality independent of the cause of CHF. However, there appeared no additional benefit of statins in patients using beta-blockers. Mortality rates were constant over time after discharge. Statins were as effective in ischemic as in nonischemic heart failure and in patients with depressed as well as preserved LVEF. CONCLUSION: Statins appear associated with improved survival in CHF independent of its etiology. No additional benefit was seen in patients treated with beta-blockers.

Adrenergic beta-Antagonists↗
PubMed2006

Statins in the treatment of chronic heart failure: biological and clinical considerations.

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.

Animals↗
PubMed2004

Statin therapy improves cardiovascular outcome of patients with peripheral artery disease.

AIMS: We sought to examine the interrelationship between statin use, inflammation, and outcome of high-risk patients with advanced atherosclerosis. METHODS AND RESULTS: We prospectively studied 515 patients with severe peripheral artery disease (median age 70 years, 296 males). The cardiovascular risk profile and laboratory parameters of inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid A [SAA], fibrinogen, serum albumin, neutrophil counts) were obtained, and patients were followed for a median of 21 months (interquartile range 12-25) for the occurrence of myocardial infarction (MI) and death. We observed 19 MIs (5 fatal and 14 nonfatal) and 65 deaths. Cumulative survival and event-free survival rates (freedom from death and MI) at 6, 12, and 24 months were 97%, 95%, and 89%, and 96%, 93% and 87%, respectively. Patients receiving statin therapy (n=269, 52%) had a lower level of inflammation (hs-CRP p<0.001, SAA p=0.001, fibrinogen p=0.007, albumin p<0.001, neutrophils p=0.049) and better survival (adjusted hazard ratio [HR] 0.52, p=0.022) and event-free survival rates (adjusted HR 0.48, p=0.004) than patients not treated with statins. However, patients with low inflammatory activity (hs-CRP < or =0.42 mg/dl) had no significant benefit from statin therapy (p=0.74 for survival; p=0.83 for event-free survival), whereas in patients with high hs-CRP (>0.42 mg/dl) statin therapy was associated with a significantly reduced risk for mortality (adjusted HR 0.58, p=0.046) and the composite of myocardial infarction and death (adjusted HR 0.46, p=0.016). CONCLUSION: Statin therapy is associated with a substantially improved intermediate-term survival of patients with severe peripheral artery disease and a high inflammatory activity, whereas in patients with low hs-CRP no survival benefit was observed.

Aged↗
PubMed2004

A combination of statins and beta-blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal myocardial infarction in patients undergoing abdominal aortic aneurysm surgery.

OBJECTIVE: To investigate the combined beneficial effect of statin and beta-blocker use on perioperative mortality and myocardial infarction (MI) in patients undergoing abdominal aortic aneurysm surgery (AAA). BACKGROUND: Patients undergoing elective AAA-surgery identified by clinical risk factors and dobutamine stress echocardiography (DSE) as being at high-risk often have considerable cardiac complication rate despite the use of beta-blockers. METHODS: We studied 570 patients (mean age 69+/-9 years, 486 males) who underwent AAA-surgery between 1991 and 2001 at the Erasmus MC. Patients were evaluated for clinical risk factors (age>70 years, histories of MI, angina, diabetes mellitus, stroke, renal failure, heart failure and pulmonary disease), DSE, statin and beta-blocker use. The main outcome was a composite of perioperative mortality and MI within 30 days of surgery. RESULTS: Perioperative mortality or MI occurred in 51 (8.9%) patients. The incidence of the composite endpoint was significantly lower in statin users compared to nonusers (3.7% vs. 11.0%; crude odds ratio (OR): 0.31, 95% confidence interval (CI): 0.13-0.74; p=0.01). After correcting for other covariates, the association between statin use and reduced incidence of the composite endpoint remained unchanged (OR: 0.24, 95% CI: 0.10-0.70; p=0.01). Beta-blocker use was also associated with a significant reduction in the composite endpoint (OR: 0.24, 95% CI: 0.11-0.54). Patients using a combination of statins and beta-blockers appeared to be at lower risk for the composite endpoint across multiple cardiac risk strata; particularly patients with 3 or more risk factors experienced significantly lower perioperative events. CONCLUSIONS: A combination of statin and beta-blocker use in patients with AAA-surgery is associated with a reduced incidence of perioperative mortality and nonfatal MI particularly in patients at the highest risk.

Adrenergic beta-Antagonists↗
PubMed2005

HMG-CoA reductase inhibitors (statins) decrease MMP-3 and MMP-9 concentrations in abdominal aortic aneurysms.

BACKGROUND: An imbalance in matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are implicated in AAA formation. 3-Hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are known to reduce MMP levels. The aim of this study was to investigate the in vivo effect of statins on MMP levels in AAA. METHODS: Infra-renal aortic biopsies were obtained from the anterior sac of 63 patients undergoing asymptomatic repair. Seventeen patients were taking a statin pre-operatively, while 46 were not. The concentrations of MMP-1, -2, -3, -8, -9, -13, TIMP-1 and TIMP-2 were quantified using ELISA. RESULTS: There was no difference in the concentration of MMP-1, -2, -8, -13, TIMP-1 or -2 in patients taking versus not taking a statin pre-operatively. In contrast levels of MMP-9 and MMP-3 were significantly lower in patients taking a statin. CONCLUSIONS: These data demonstrate that statins decrease MMP-9 and MMP-3 levels and represent a potential pharmacotherapy in established AAA.

Aged↗
PubMed2006

Can statins reduce perioperative morbidity and mortality in patients undergoing non-cardiac vascular surgery?

AIMS: To determine whether statins can reduce perioperative morbidity and mortality in patients undergoing non-cardiac vascular surgery. METHODS: A search using Pubmed was performed to identify reports in English. The search terms were: "statins", "perioperative morbidity", "perioperative mortality" and "vascular surgery". We excluded studies dealing with the effect of statins in cardiac surgery. Retrieved articles were manually searched. RESULTS: Current evidence shows that statins decrease perioperative morbidity and mortality in patients undergoing non-cardiac vascular surgery. Any benefit probably occurs soon (within a month) after initiating treatment. CONCLUSIONS: Appropriately designed trials need to confirm the beneficial effect of perioperative statin therapy in various patient categories. The optimal duration and dose of perioperative statin therapy should be defined.

Adrenergic beta-Antagonists↗
PubMed2005

The effect of preoperative statin therapy on cardiovascular outcomes in patients undergoing infrainguinal vascular surgery.

BACKGROUND: Patients undergoing vascular surgery are at increased risk for perioperative cardiovascular (CV) complications. Our goal was to determine the effect of preoperative statin therapy on perioperative cardiac and vascular outcomes, and long-term survival in patients undergoing infrainguinal vascular bypass surgery. METHODS: We retrospectively reviewed consecutive infrainguinal vascular bypass surgeries on 446 patients performed between 1995-2001 at the University of Chicago Medical Center. Information was collected on preoperative statin and beta-blocker use, baseline characteristics, perioperative cardiac and major vascular complications, and length of stay (LOS). Long-term survival was assessed using the Social Security Death Index (SSDI). RESULTS: Thirty day perioperative complications included all-cause mortality (2.5%), CV mortality (1.8%), myocardial infarction (MI) (4.7%), stroke (1.1%), and major peripheral vascular complications (12.8%), and the composite of cardiac and vascular complications [combined CV complications] (17.9%). Statin therapy was associated with fewer combined CV complications (6.9% vs 20.1%, p=0.008), and a shorter LOS (6.4 vs 9.7 days, p=0.007). On multivariate logistic regression analysis, adjusting for significant baseline characteristics including beta-blocker use, statin therapy was independently associated fewer combined CV complications (odds ratio (OR) 0.36, 95% confidence interval (CI) 0.14-0.93, p=0.035) and a shorter LOS (OR 1.49, 95% CI 1.14-1.95, p=0.003). In a mean follow up period of 5.5 years, 215 deaths (48%) occurred. Statin therapy was independently associated with improved long-term survival (OR 0.52, 95% CI 0.32-0.84, p<0.004), after adjusting for significant baseline characteristics. CONCLUSION: Preoperative statin therapy is associated with fewer combined perioperative cardiac and major vascular complications, a shorter length of stay, and improved long-term survival in patients undergoing infrainguinal vascular bypass surgery.

Adrenergic beta-Antagonists↗
PubMed2005

Key factors associated with the under-prescription of statins in elderly coronary heart disease patients: Results from the ELIAGE and ELICOEUR surveys.

INTRODUCTION: The reasons why statins are under-utilized in elderly patients remain poorly understood. The aim of this study was to identify the reasons given by cardiologist for the non-prescription of statins in elderly CHD patients. METHODS: Two cross-sectional pharmaco-epidemiological surveys were carried out among French cardiologists. The sample consisted of 1148 coronary patients aged 35 to 69 years and 1489 patients aged > or =70 years. Patients' risk factors, medical history, treatments, lipid values and the physicians' various motives for the non-prescription of statins were recorded. RESULTS: Patients not treated with statins reached 37% in the age-group > or =70 years and 14% in the age-group 35-69 years. The main reason given for statin non-prescription was the lack of a medical indication (2.5% of the age-group 35-69 years and 14% of the age-group > or =70 years). Among patients > or =70 years, the lack of indication was more often cited in the following conditions: 1) in very old patients (36% of lack of indication in the age-group >85 years vs. 10% in 70-75 years), 2) when lipid values were not available (20% when data were not available vs. 9%) and 3) when the patient had no prior history of myocardial infarction (MI) (20% when no history of MI vs. 7%). These factors were not associated with lack of indication among patients <70 years. History of intolerance or side effect was given for 1.3% and 14% of patients for each of the groups (35-69 and > or =70) and poor overall patient adherence was cited in 1% and 2%, respectively. CONCLUSION: The primary reason for the under-prescription of statins in elderly coronary patients is the perceived lack of indication, which stresses the need of extensive guidelines for prescription in elderly patients. Several factors associated with this perception seem to be specific to the elderly.

Adult↗
PubMed2006

The effect of statin on the aortic gene expression profiling.

BACKGROUND: Beyond lipid lowering, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) has been found to have anti-inflammatory and anti-thrombotic effects. However, the genetic expression pattern changes in atherosclerotic lesions produced by statin are rarely studied. METHODS: Cholesterol-fed apolipoprotein (Apo) E-deficient mice were examined for the treatment effect of statin on aortic gene expression. ApoE-deficient mice were fed with a hypercholesterolemic diet started at 8 weeks of age for a total of 22 weeks. In the statin treatment group (n=25), the ApoE-deficient mice were treated with pravastatin (80 mg/kg/day) dissolved in water by daily oral inoculation from 25 to 30 weeks of age. For the control group (n=25), the ApoE-deficient mice were orally inoculated with water only for the same period of time. The aortic gene expression affected by pravastatin was identified using oligonucleotide microarray technology with Agilent gene chips. RESULTS: The total cholesterol and atherosclerotic lesion/total aortic area were significantly lower in the pravastatin treatment group. Microarray analysis of the expression of 20,281 murine genes in the aortas between the two groups indicated that 94 genes were significantly regulated. Thirty genes were up-regulated and 64 genes were down-regulated. The most up-regulated genes were troponin T3, actin alpha1, tubulin alpha1, regulator of G-protein signaling 5 (Rgs5), stathmin-like 2 and myosin light chain kinase. Most of them are related with cytoskeleton organization, while Rgs5 is a G-protein signal transduction molecule. The most down-regulated genes were adenosine deaminase, atrial natriuretic peptide, troponin T2, FXYD domain-containing ion transport regulator 3, and glutathione S-transferase alpha4. CONCLUSIONS: The beneficial effect of the 6-week statin treatment in ApoE-deficient mice is largely dependent on its influence on the cytoskeleton organization. Our study results might provide insight into the clinical benefits of chronic statin treatment.

Animals↗
PubMed2005

Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis.

OBJECTIVES: This study sought to determine whether statins reduce coronary heart disease (CHD) risk more than other interventions that also primarily lower low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Statins have anti-inflammatory, immunomodulatory, antithrombotic, vascular, and other non-LDL-C-lowering effects. It is unclear whether these pleiotropic effects contribute to cardiovascular risk reduction beyond that expected from LDL-C reduction alone. METHODS: Trials published in English language journals were retrieved by searching Medline (1966 to October 2004), bibliographies, and the author's reference files. Randomized, placebo-controlled trials of interventions to primarily lower LDL-C of three or more years' duration in which clinical disease or death were primary outcomes were used. Information on sample size, treatment type and duration, participant characteristics at baseline, reduction in lipids, and outcome was independently abstracted by two authors (J.R. and N.M.) using a standardized protocol. Data from 5 diet, 3 bile acid sequestrant, 1 surgery, and 10 statin trials, with 81,859 participants, were included in the CHD meta-regression analysis. RESULTS: The regression lines for non-statin and statin trials were similar and consistent with a one-to-one relationship between LDL-C lowering and CHD and stroke reduction over five years of treatment. CONCLUSIONS: The pleiotropic effects of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-C lowering observed in other trials that primarily lowered LDL-C.

Cholesterol, LDL↗
PubMed2006

Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study.

OBJECTIVES: We aimed to determine whether intensive statin therapy reduces hospitalization for heart failure (HF) in high-risk patients. BACKGROUND: While the relationship between intensive statin therapy and ischemic events is well established, its relationship to the risk of HF after an acute coronary syndrome (ACS) is not well defined. METHODS: The Pravastatin or Atorvastatin Evaluation and Infection Trial-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study randomized 4,162 patients, stabilized after ACS, to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 days after randomization was determined during a mean follow-up of 24 months. B-type natriuretic peptide (BNP) levels were measured at baseline (median seven days after randomization). RESULTS: Treatment with atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (2.3% vs. 3.9%, [corrected] hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.45 to 0.91, p = 0.012) [corrected] independently of a recurrent myocardial infarction or prior history of HF. The risk of HF increased steadily with increasing quartiles of BNP (HR 2.45, 95% CI 1.33 to 4.52, p = 0.004 [corrected] for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (>80 pg/ml), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR 0.50, 95% CI 0.27 to 0.93, p = 0.028). [corrected]. A meta-analysis of four trials that included 27,546 patients demonstrates a 27% reduction in the odds of hospitalization for HF with intensive statin therapy. CONCLUSIONS: Intensive statin therapy reduces the risk of hospitalization for HF after ACS with the most gain in patients with elevated levels of BNP.

Acute Disease↗
PubMed2005

Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition.

BACKGROUND: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro. METHODS: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 micromol/L and 30 micromol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis. RESULTS: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 +/- 3.5 microm vs control group, 64.0 +/- 7.1 microm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. CONCLUSIONS: These novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting. CLINICAL RELEVANCE: Late graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting.

Animals↗
PubMed2005

Association between reduced low density lipoprotein oxidation and inhibition of monocyte chemoattractant protein-1 production in statin-treated subjects.

Monocyte chemoattractant protein-1 (MCP-1) is essential in atherogenesis. Oxidized lipids regulate MCP-1 expression and release from mononuclear cells. In this study we investigated (1) whether statin therapy reduces lipopolysaccharide (LPS)-stimulated MCP-1 production in human whole-blood samples and (2) the relationships between in vitro low-density lipoprotein (LDL) oxidation and MCP-1 production. Fasting blood samples were obtained from 55 healthy nonsmoking adults with moderate hypercholesterolemia who were participating in a randomized double-blind 8-week trial comparing the effects of statin therapy with those of placebo on cytokine production. Samples were analyzed for resistance to copper-mediated LDL oxidation (lag time in minutes), as well as MCP-1- and interleukin-8 (IL-8)-stimulated production. Statin therapy reduced MCP-1 production (mean +/- SD) -161 +/- 399 pg/mL/mm 3 white cells) compared with 267 +/- 985 pg/mL/mm 3 in the placebo group, but changes were not different between active and placebo groups ( P = .13). Statin therapy also increased lag times (median [interquartile range]; 20.5 [7.0-51.2] minutes vs -17.0 [-5.3-16.5] minutes; P = .067 for group difference). Inhibition of MCP-1 production correlated with prolongation of lag time ( r = .46, P = .0056) in statin-treated subjects. Statin therapy reduced MCP-1 production in the whole blood of human subjects and these changes were correlated with improvement in LDL oxidative resistance.

Adult↗
PubMed2006

Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway.

Statins are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that function as potent inhibitors of cholesterol biosynthesis and have been used for many years for the treatment of hypercholesterolemia. However, accumulating experimental and clinical studies have revealed that the health benefits associated with statins treatment, particularly those conferred on the cardiovascular system, were the cholesterol-independent. 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 postranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. The isoprenylation of Rho is a prerequisite for Rho activation, facilitating its interaction with the plasma membrane, undergoing GDP-GTP exchange and be activated. Inhibition of RhoA geranylgeranylation by statins decreases membrane GTP-bound active RhoA and subsequent Rho-kinase activity. Activated RhoA via its downstream effector Rho-kinase is involved in a wide range of cellular functions, such as cell migration, proliferation and apoptosis. Recently, rising evidences suggested that RhoA/Rho-kinase pathway was essentially involved in various models of pulmonary hypertension and statins effectively ameliorated pulmonary hypertension. Based on this findings, we hypothesis that statins attenuate pulmonary hypertension via RhoA/Rho-kinase signaling pathway in vivo.

Animals↗