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PubMed2000

Effect of statin therapy on restenosis after coronary stent implantation.

The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation.

Anticholesteremic Agents↗
PubMed2004

Association of dyslipidemia and effects of statins on nonmacrovascular diseases.

BACKGROUND: Statins have mechanisms of action that expand their effects beyond cholesterol lowering and atherosclerotic medical conditions. OBJECTIVE: This review summarizes clinical evidence for the association of dyslipidemia and the effects of statin use on aortic stenosis, Alzheimer's dementia (AD), osteoporosis, prevention of diabetes mellitus (DM), diabetic retinopathy, age-related macular degeneration, and diabetic/nondiabetic nephropathy. METHODS: An English-language literature search was conducted using MEDLINE (1966-June 2003). Bibliographies of retrieved articles were reviewed. Search terms included statin, HMG-CoA reductase inhibitors, aortic stenosis, Alzheimer's dementia, osteoporosis, prevention of diabetis, diabetic retinopathy, age-related macular degeneration, diabetic nephropathy, and nondiabetic nephropathy. RESULTS: Three retrospective cohort trials have shown an association between statin use and the progression of aortic stenosis; one of these trials observed a 45% decrease in aortic valve area in 1 year. In AD, one cross-sectional analysis found 60% to 73% lower AD rates in lovastatin or pravastatin recipients ( P<0.001 ). Of the multiple observational studies on the effect of statins on fracture risk, some have shown a decreased risk, with an odds ratio as low as 0.50 (95% CI, 0.33-0.76); others have demonstrated no association. A post hoc analysis of the West of Scotland Coronary Prevention Study found a 30% reduction in the development of DM ( P=0.042 ), but this was not duplicated in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. A small clinical trial of 6 patients (11 eyes) demonstrated improved retinal hard exudates with pravastatin treatment in patients with diabetic retinopathy. In a cross-sectional analysis, age-related macular degeneration was found to be less common among statin users than nonusers (4% [ 1/27 ] vs 22% [ 76/352 ]; P=0.02. Multiple small clinical trials of 19 to 56 patients with diabetic and nondiabetic nephropathy at various stages generated inconsistent results for an association between statin use and decreased albumin excretion rate and decreased rate of decline in glomerular filtration. CONCLUSION: Data of variable quantity and quality support the use of statins as adjuncts in the treatment of nonmacrovascular diseases.

Alzheimer Disease↗
PubMed2000

Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease.

OBJECTIVES: The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). BACKGROUND: Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. METHODS: Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. RESULTS: Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). CONCLUSIONS: Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.

Aged↗
PubMed2002

Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels.

OBJECTIVES: We sought to estimate the potential gains in life expectancy achieved with statin therapy for individuals without overt hyperlipidemia but with elevated C-reactive protein (CRP) levels. BACKGROUND: Persons with low-density lipoprotein (LDL) cholesterol levels below current treatment guidelines and elevated CRP levels are at increased risk of cardiovascular disease and may benefit from statin therapy. METHODS: We constructed a decision-analytic model to estimate the gains in life expectancy with statin therapy for individuals without overt hyperlipidemia but with elevated CRP levels. The annual risks of myocardial infarction (MI) and stroke, as well as the efficacy of statin therapy, were based on evidence from randomized trials. Estimates of prognosis after MI or stroke were derived from population-based studies. RESULTS: We estimated that 58-year-old men and women with CRP levels >or=0.16 mg/dl but LDL cholesterol <149 mg/dl would gain 6.6 months and 6.4 months of life expectancy, respectively, with statin therapy. These gains were similar to those for patients with LDL cholesterol >or=149 mg/dl (6.7 months for men and 6.6 months for women). In sensitivity analyses, we identified the baseline risk of MI and the efficacy of statin therapy for preventing MI as the most important factors in determining the magnitude of benefit with statin therapy. CONCLUSIONS: Our results suggest that individuals with elevated CRP levels, many of whom do not meet current National Cholesterol Education Program guidelines for drug treatment, may receive a substantial benefit from statin therapy. This analysis supports a crucial need for direct intervention trials aimed at subjects with elevated CRP levels.

C-Reactive Protein↗
PubMed2003

Long-term statin use and psychological well-being.

OBJECTIVES: We sought to study the effect of long-term statin use on psychometric measures in an adult population with underlying coronary artery disease (CAD). BACKGROUND: Previous studies have suggested associations between cholesterol lowering and psychological well-being. METHODS: Study subjects were recruited from an outpatient cardiology clinic. Psychological well-being was assessed at baseline and annually during follow-up. The exposure of interest was long-term statin use and the outcomes of interest were depression, anxiety, and hostility. We estimated the odds ratios (ORs) and 95% confidence intervals (CI) that represented the strength of association between statin use (vs. no use of any cholesterol-lowering drug) and the risk of having abnormal depression, anxiety, and hostility scores. RESULTS: Study subjects had an average follow-up of four years and maximum of seven years. Comparing the 140 patients who had continuous use of statins with the 231 patients who did not use any cholesterol-lowering drugs, statin use was associated with lower risk of abnormal depression scores (OR 0.63, 95% CI 0.43 to 0.93), anxiety (OR 0.69, 95% CI 0.47 to 0.99), and hostility (OR 0.77, 95% CI 0.58 to 0.93) after adjustment for the propensity for statin use and potential confounders. The beneficial psychological effects of the statins appeared to be independent of the drugs' cholesterol-lowering effects. CONCLUSIONS: Long-term use of statins among patients with CAD appeared to be associated with reduced risk of anxiety, depression, and hostility.

Adaptation, Physiological↗
PubMed2006

[Statins in patients with kidney failure: efficacy, tolerance, and prescription guidelines in patients with chronic kidney disease and renal transplant].

BACKGROUND: Chronic kidney disease (CKD) is extremely common in adults, although often undiagnosed and thus untreated. Cardiovascular disease is the leading cause of death among patients with CKD and reducing its risk in this population is an important priority. Dyslipidemia is almost always present when proteinuria is above 3 gr/24 hours. Roughly two thirds of all patients with end-stage renal failure and kidney transplants suffer from dyslipidemia and should receive lipid-lowering therapy, as suggested by recent Afssaps (French drug agency) and NKF-K/DOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines. We reviewed recent studies on efficacy, tolerability and prescription recommendations of statins in CKD and renal transplant patients. METHODS: We searched Medline, the international medical database, to conduct a systematic review of the literature on the efficacy and tolerability of statins in CKD and renal transplant patients and on specific recommendations for dosage adjustments in this population. RESULTS: The efficacy of statins in decreasing total cholesterol and LDL-cholesterol levels in dialysis and renal transplant patients is similar to that in the general population. On the other hand, large-scale randomized clinical trials among CKD (4D) and renal transplant (ALERT) patients do not demonstrate that statins significantly decrease rates of cardiovascular disease. They have a beneficial effect on proteinuria and lower the rate of kidney function deterioration in patients with dyslipidemia. Early introduction of a statin in transplant patients did not lead to improved kidney function or prevent loss of the graft. Although most statins are not excreted by the kidneys, the dosage of some must be adapted in CKD patients because of pharmacokinetic modifications induced by renal impairment. CONCLUSION: Statins at appropriately adapted doses have the same efficacy in CKD patients as in subjects with normal kidney function, and tolerance is not a problem. Their effectiveness in cardiovascular prevention in this population has not been demonstrated to date. Results about statin-induced kidney protection are encouraging but further and more specific studies are needed.

Adult↗
PubMed2000

Early experience with intravascular ultrasound in evaluating the effect of statins on femoropopliteal arterial disease: hypothesis-generating observations in humans.

The purpose of this study was to compare the vascular response seen with intravascular ultrasound (IVUS) at 1-year follow-up between statin-treated and non-statin-treated patients. Patients (n = 10) undergoing percutaneous transluminal angioplasty (PTA) of the femoropopliteal artery were studied with IVUS immediately after PTA and at 1-year follow-up. In nondilated matched vascular segments, the change in lumen, vessel, and plaque volume was assessed. In balloon-dilated matched vascular segments, the change in lumen, vessel, and plaque area was assessed. A comparison was made between statintreated (n = 5) and non-statin-treated patients (n = 5) in lumen, vessel, and plaque changes. At follow-up, both statin-treated and non-statin-treated patients showed a similar increase in plaque volume at the nondilated segment (+4% and +2%, respectively). In statin-treated patients the plaque volume increase was compensated by an increase in vessel volume (+2%), resulting in an increase in lumen volume (+1%). In non-statin-treated patients, on the other hand, the increase in plaque volume was associated with a decrease in vessel volume (-2%), resulting in a decrease in lumen volume (-4%). At the balloon-dilated segment a similar trend in changes of lumen, vessel, and plaque was encountered. Differences between both groups of patients were not statistically significant. Despite the nonsignificant nature of the observation, this small retrospective IVUS study may generate the hypothesis that statin therapy may contribute to superior long-term lumen dimensions by inducing positive vascular remodeling both in nondilated and balloon-dilated vascular segments.

Adult↗
PubMed2003

Statins and the role of nitric oxide in chronic heart failure.

Endothelial dysfunction plays an important role in a number of cardiovascular diseases. An important pathogenetic factor for the development of endothelial dysfunction is lack of nitric oxide (NO), which is a potent endothelium-derived vasodilating substance. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), originally designed to lower plasma cholesterol levels, seem to ameliorate endothelial dysfunction by a mechanism so far only partly understood. However, statins increase nitric oxide synthase activity. It has been speculated that this and other "side effects" of statin treatment are due to inhibition of Rho, an intracellular signalling protein that initiates Rho kinase transcription. Moreover, statins possess anti-inflammatory characteristics. Some statins have proven to lower plasma levels of C-reactive protein, which is induced by pro-inflammatory cytokines. Other statins have been demonstrated to directly inhibit pro-inflammatory cytokine induction. Finally, some data suggest that statins might be able to counterbalance an increased production of oxygen free radicals. Since chronic heart failure is accompanied not only by endothelial dysfunction, but also by pro-inflammatory cytokine activation and enhanced formation of oxygen free radicals, it is tempting to speculate that statins might be an ideal candidate to treat certain features of this disease. The doses needed to achieve the desired effects might be much lower than those needed to treat hypercholesterolemia.

Cholesterol, LDL↗
PubMed2000

Inhibition of small G proteins of the rho family by statins or clostridium difficile toxin B enhances cytokine-mediated induction of NO synthase II.

In order to investigate the involvement of Ras and/or Rho proteins in the induction of the inducible isoform of nitric oxide synthase (NOS II) we used HMG-CoA reductase inhibitors (statins) and Clostridium difficile toxin B (TcdB) as pharmacological tools. Statins indirectly inhibit small G proteins by preventing their essential farnesylation (Ras) and/or geranylgeranylation (Rho). In contrast, TcdB is a glucosyltransferase and inactivates Rho-proteins directly. Human A549/8- and DLD-1 cells as well as murine 3T3 fibroblasts were preincubated for 18 h with statins (1 - 100 microM) or TcdB (0.01-10 ng ml(-1)). Then NOS II expression was induced by cytokines. NOS II mRNA was measured after 4 - 8 h by RNase protection assay, and NO production were measured by the Griess assay after 24 h. Statins and TcdB markedly increased cytokine-induced NOS II mRNA expression and NO production. Statin-mediated enhancement of NOS II mRNA expression was reversed almost completely by cotreatment with mevalonate or geranylgeranylpyrophosphate. It was only slightly reduced by farnesylpyrophosphate. Therefore, small G proteins of the Rho family are likely to be involved in NOS II induction. In A549/8 cells stably transfected with a luciferase reporter gene under the control of a 16 kb fragment of the human NOS II promoter (pNOS2(16)Luc), statins produced only a small increase in cytokine-induced NOS II promoter activity. In contrast, statins had a considerable superinducing effect in DLD-1 cells stably transfected with pNOS2(16)Luc. In conclusion, our studies provide evidence that statins and TcdB potentiate cytokine-induced NOS II expression via inhibition of small G proteins of the Rho family. This in turn results in an enhanced NOS II promoter activity and/or a prolonged NOS II mRNA stability.

3T3 Cells↗
PubMed2001

The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor.

The prostanoid-IP receptor may be unique among G protein coupled receptors in that it is isoprenylated. In this study, we investigated the effects of the statins lovastatin and cerivastatin on signalling by the mouse (m) IP and the human (h) IP receptors, over-expressed in human embryonic kidney (HEK) 293 cells and by the hIP receptor, endogenously expressed in human erythroleukaemia cells. Both statins significantly reduced IP receptor-mediated cyclic AMP generation and intracellular calcium ([Ca(2+)](i)) mobilization in a time and concentration dependent manner but had no effect on signalling by the non-isoprenylated beta(2) adrenergic receptor or by the human prostanoid-TP receptor isoforms. Cerivastatin (IC(50), 50 - 90 nM) was significantly more potent than lovastatin (IC(50), 0.80 - 4.2 microM) in inhibiting IP receptor signalling. Whereas IC(50) values indicated that the hIP receptor was significantly more sensitive than the mIP receptor to the statins, the extent of inhibition of cyclic AMP generation by the mIP receptor was significantly greater than that of the hIP receptor to either statin, even at the highest concentrations used. Pretreatment with either statin significantly reduced IP receptor mediated desensitization of signalling by the h.TPalpha, but not by the h.TPbeta, receptor isoform. These data generated in whole cells point to the possibility that statin therapy may interfere with IP receptor signalling in vivo; such interference may be extenuated under conditions where circulating statin levels are elevated and may account, in part, for some of the pleiotropic affects of the statins not attributed solely to their lipid lowering properties.

Anticholesteremic Agents↗
PubMed2005

Statins and stroke.

Inhibitors of HMG-CoA reductase (statins) are potent cholesterol-lowering drugs. Large clinical trials have shown that statins reduce the incidence of cerebrovascular events, which might be surprising because cholesterol is not an established risk factor for stroke. In addition to their cholesterol-lowering properties, statins exert a number of pleiotropic, vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, inhibition of inflammatory responses, immunomodulatory actions, regulation of progenitor cells, and stabilization of atherosclerotic plaques. In fact, statins augment cerebral blood flow and confer significant protection in animal models of stroke partly via mechanisms related to the upregulation of endothelial nitric oxide synthase. Retrospective clinical evidence suggests that long-term statin administration may not only reduce stroke risk but also improve outcome. Early secondary prevention trials are underway to test the hypothesis that statin treatment initiated immediately after an event improves short-term outcome. Lastly, recent evidence suggests that sudden discontinuation of statin treatment leads to a rebound effect with downregulation of NO production. Withdrawal of statin treatment may impair vascular function and increase morbidity and mortality in patients with vascular disease.

Animals↗
PubMed2002

Microcirculation as a target for the anti-inflammatory properties of statins.

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a ubiquitous enzyme critical for the biosynthesis of cholesterol. Because of their cholesterol-lowering properties, statins are extensively used in medical practice, and large clinical trials have shown that statins effectively reduce cardiovascular related morbidity and mortality. In the past 5 years, an important, new concept suggesting that the cardioprotective effects of statins are not necessarily related to cholesterol-lowering actions has emerged. Indeed, in vivo findings have clearly shown that statins exert anti-inflammatory and immunomodulatory effects and that they modulate vascular remodeling under normocholesterolemic conditions. These pleiotropic properties of statins affect important molecules in vascular biology and help preserve endothelial function in acute and chronic inflammatory states of the cardiovascular system, including coronary and cerebral artery diseases, diabetes, and atherosclerosis. Emerging evidence indicates that the microcirculation is a crucial target for the pleiotropic actions of statins because of its important role in regulating blood flow, leukocyte-endothelium interactions, and vascular remodeling. Accordingly, this review focuses on the role that the microcirculation plays in the vascular protective action of statins.

Anti-Inflammatory Agents↗
PubMed2001

Statins for primary prevention: at what coronary risk is safety assured?

AIMS: Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients. METHODS: The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method. RESULTS: The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin's beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years. CONCLUSIONS: Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.

Coronary Disease↗
PubMed2002

Statins decrease bone turnover in postmenopausal women: a cross-sectional study.

BACKGROUND: Statins have been suggested as potential agents in the management of osteoporosis. Reviews of medical records have shown an increased bone mass and some studies have shown a reduced occurrence of fractures in subjects on long-term treatment with statins. We studied the effects of treatment with statins on calcium homeostasis, bone turnover and bone mineral density. DESIGN: In a cross-sectional design, plasma levels of parathyroid hormone (PTH) and biochemical markers of bone turnover, bone mineral density (BMD) and body composition (fat- and lean tissue-mass) were measured in 140 postmenopausal women who had been treated with a statin for more than 2 years (median 4 years) and compared to 140 age- and gender-matched, population-based controls. RESULTS: Plasma levels of bone turnover markers were lower in the statin-treated subjects than in the controls: osteocalcin (-9%, P = 0.03), bone-specific alkaline phosphatase (-14%, P < 0.01), and C-terminal telopeptide of type I collagen (-11%, P < 0.01). On the other hand, plasma PTH levels were 16% higher in the statin-treated subjects than in the controls (P < 0.01). However, body composition and BMD at the lumbar spine, hip, forearm and whole body did not differ between the two groups. No correlation could be demonstrated between changes in biochemical quantities and dose or duration of statin use. CONCLUSION: Our data show that statins affect the function of bone cells. Most likely, the effect is antiresorptive.

Aged↗
PubMed2004

Effects of statins on endothelium and endothelial progenitor cell recruitment.

Statins appear to be potent drugs with a variety of pleiotropic effects with vasculoprotective and cardioprotective activity. The beneficial effects of statins on endothelial cells as well as on endothelial cell function appear to be related to improved nitric oxide bioavailability. Mechanistically, statins induce endothelial nitric oxide synthase mRNA stability in endothelial cells and promote endothelial nitric oxide synthase activity through a PI3K/Akt dependent pathway, which is a common signal transduction pathway shared by growth factors such as vascular endothelial growth factors or fibroblast growth factors (FGFs), estrogens, or statins. Furthermore, statins have potent antiinflammatory capacities by potently interfering with the generation of reactive oxygen species or activating scavenging systems for free radicals such as the thioredoxin system. These mechanisms might all contribute to improved NO bioavailability and confer the beneficial actions of statins. The proangiogenic properties of statins and their effects on reendothelialization following vessel injury include novel actions such as the mobilization, differentiation, and improved survival of endothelial progenitor cells. Statin therapy might reverse the impaired functional regeneration capacities seen in patients with risk factors for coronary artery disease or documented active coronary artery disease by specifically interacting with progenitor cell function. Accordingly, augmentation of functionally active endothelial progenitor cells with improved homing capacity will be a critical step in advancing therapeutic neovascularization as well as reendothelialization in patients with coronary artery disease.

Animals↗
PubMed2006

Effects of preoperative statin therapy on cytokines after cardiac surgery.

INTRODUCTION: In addition to their lipid-lowering action, it has been demonstrated that statins can exert direct anti-inflammatory effects. We investigated the effect of preoperative statin therapy on systemic inflammatory markers and myocardial NF-kappaB inhibitor IkappaB-alpha after cardiac surgery. METHODS: Thirty-six patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass (CPB) with cardioplegia were divided into two groups (statin group, n = 18; control group, n = 18). Plasma concentrations of pro-inflammatory cytokines (tumor necrosis factor alpha [TNFalpha], interleukin [IL]-6, IL-8) and anti-inflammatory IL-10 were measured before and 1, 4, 10, and 24 hours (h) after CPB. Phosphorylated IkappaB-alpha/total IkappaB-alpha ratio was assessed before and after CPB in right atrial biopsies. RESULTS: Baseline and operative data did not differ between groups. Statin therapy was associated with lower preoperative low-density lipoprotein levels compared to control (73+/-6 vs. 92+/-6 mg/dL; P=0.03). Release of IL-6 was attenuated in the statin group at 4 h (2270+/-599 vs. 5120+/-656 pg/ml; P<0.01) and 10 h (1295+/-445 vs. 3116+/-487 pg/ml; P<0.05) compared to the control group. IL-10 increased after surgery in both groups (P<0.05), but was higher in the statin group at 1 h (66+/-15 vs. 26+/-16 pg/mL; P<0.01). Phosphorylated IkappaB-alpha/total IkappaB-alpha ratio before CPB did not differ between groups, but was elevated after CPB in both groups (P<0.05), indicating enhanced degradation of IkappaB-alpha. Statin therapy had no effect on TNFalpha and IL-8. CONCLUSIONS: Preoperative statin therapy attenuates the release of pro-inflammatory IL-6 and up-regulates anti-inflammatory IL-10 after cardiac surgery with cardioplegia, but fails to inhibit phosphorylation of myocardial IkappaB-alpha.

Aged↗
PubMed2005

Statins exert endothelial atheroprotective effects via the KLF2 transcription factor.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, have been shown to positively impact vascular function independent of their plasma lipid-lowering action. Several of these beneficial effects involve modulation of gene expression. Here we explored whether the transcription factor Kruppel-like factor 2 (KLF2), a biomechanically activated gene we recently identified as part of the endothelial "atheroprotective phenotype," is regulated by statins and whether this mechanism is important for the non-lipid lowering beneficial effects mediated by these drugs in endothelium. The mRNA levels of KLF2 in human umbilical vein endothelial cells increased in the presence of various statins. KLF2 induction was observed within 8 h after drug treatment and remained elevated for at least 24 h. This statin effect on KLF2 expression was reversed by addition of mevalonate and its downstream metabolite geranygeranyl pyrophosphate. Furthermore, inhibition of protein geranylgeranylation with GGTI-298 significantly induced KLF2 levels, whereas inhibition of farnesylation did not. Statin-mediated KLF2 expression was followed by the up-regulation of several of its downstream transcriptional targets. Using small interfering RNA to block KLF2 expression, we demonstrated that this transcription factor is necessary for the statin-mediated regulation of several pathophysiologically relevant genes. These results strongly implicate KLF2 as a transcriptional regulator of the statin-mediated effects in vascular endothelium and provide a novel mechanism for the well established non-lipid lowering beneficial cardiovascular effects of statins.

Arteriosclerosis↗
PubMed2004

Statins suppress oxidized low density lipoprotein-induced macrophage proliferation by inactivation of the small G protein-p38 MAPK pathway.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) ameliorate atherosclerotic diseases. Macrophages play an important role in the development and subsequent stability of atherosclerotic plaques. We reported previously that oxidized low density lipoprotein (Ox-LDL) induced macrophage proliferation through the secretion of granulocyte/macrophage colony-stimulating factor (GM-CSF) and the consequent activation of p38 MAPK. The present study was designed to elucidate the mechanism of the inhibitory effect of statins on macrophage proliferation. Mouse peritoneal macrophages were used in our study. Cerivastatin and simvastatin each inhibited Ox-LDL-induced [(3)H]thymidine incorporation into macrophages. Statins did not inhibit Ox-LDL-induced GM-CSF production, but inhibited GM-CSF-induced p38 MAPK activation. Farnesyl transferase inhibitor and geranylgeranyl transferase inhibitor inhibited GM-CSF-induced macrophage proliferation, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the effect of statins. GM-CSF-induced p38 MAPK phosphorylation was also inhibited by farnesyl transferase inhibitor or geranylgeranyl transferase inhibitor, and farnesyl pyrophosphate and geranylgeranyl pyrophosphate prevented the suppression of GM-CSF-induced p38 MAPK phosphorylation by statins. Furthermore, we found that statin significantly inhibited the membrane translocation of the small G protein family members Ras and Rho. GM-CSF-induced p38 MAPK activation and macrophage proliferation was partially inhibited by overexpression of dominant negative Ras and completely by that of RhoA. In conclusion, statins inhibited GM-CSF-induced Ras- or RhoA-p38 MAPK signal cascades, thereby suppressing Ox-LDL-induced macrophage proliferation. The significant inhibition of macrophage proliferation by statins may also explain, at least in part, their anti-atherogenic action.

Animals↗