HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins' beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent "pleiotropic" properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins' CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.

Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22(phox) and gp91(phox) mRNA expression, and myocardial 8-iso-prostaglandin F(2α) (PGF(2α)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV dP/dt, 8.9 ± 1.8 vs 5.4 ± 1.0 × 10(3) mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22(phox) and gp91(phox) mRNA expression and myocardial PGF(2α) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 ± 13.2 vs 48.6 ± 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 ± 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor.

Increased oxidative stress might contribute to diabetic (DM) neuropathy, so the effects of long-term treatment with fluvastatin (FL) on myocardial oxidative stress and cardiac sympathetic neural function were investigated in diabetic rats.

FL (10 mg . kg(-1) . day(-1), DM-FL) or vehicle (DM-VE) was orally administered for 2 weeks to streptozotocin-induced DM rats. Cardiac oxidative stress was determined by myocardial 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) and NADPH oxidase subunit p22(phox) mRNA expression. Sympathetic neural function was quantified by autoradiography using (131)I- and (125)I-metaiodobenzylguanidine (MIBG). FL did not affect plasma glucose levels but remarkably decreased PGF(2alpha) levels compared with DM-VE rats (13.8+/-9.2 vs 175.0+/-93.9 ng/g tissue), although PGF(2alpha) levels were below the detection limit in non-DM rats. FL significantly reduced myocardial p22(phox) mRNA expression. Cardiac (131)I-MIBG uptake was lower in DM-VE rats than in non-DM rats, but the decrease was attenuated in DM-FL rats (1.31+/-0.08, 1.88+/-0.22, and 1.58+/-0.18 %kg dose/g, respectively, P<0.01). Cardiac MIBG clearance was not affected by the induction of DM or by FL, indicating that the reduced MIBG uptake in DM rats might result from impaired neural function.

FL ameliorates cardiac sympathetic neural dysfunction in DM rats in association with attenuation of increased myocardial oxidative stress.

We examined effects of a physiologic concentration of pitavastatin (0.01 micromol/L) on oxidant-induced apoptosis in cultured human vascular smooth muscle cells (VSMCs). Apoptosis was induced in VSMCs by hydrogen peroxide (H2O2, 300 micromol/L), as evidenced by in situ nick end-labeling and scanning electron microscopy. This apoptotic response was accompanied by increased activation of mitogen-activated protein kinases (MAPKs--ie, increases in the phosphorylated forms of extracellular signal-regulated kinase (p-ERK), c-Jun N-terminal kinase (p-JNK), and p38 MAPK (p-p38 MAPK). Although pitavastatin alone did not induce VSMC death, pretreatment with pitavastatin significantly enhanced H2O2-induced apoptosis and prolonged activation of JNK and p38 MAPK (for up to 24 h) but not ERK. Expression of MAPK phosphatase-1 (MKP-1) also was upregulated by H2O2, but this was not affected by pitavastatin. The apoptosis accelerating effect was observed also in simvastatin but not in pravastatin. Treating VSMCs with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate completely blocked the statin-induced enhancement of VSMC apoptosis, suggesting that protein prenylation is critically involved. It thus appears that pitavastatin enhances H2O2-induced VSMC apoptosis, at least in part, via increases in MAPK activation and protein prenylation, but independently of MKP-1 expression, which consequently results in reduction of VSMC population.

Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-9 were reported to be expressed at the macrophage-rich area in human coronary atherosclerotic plaque. We examined whether C-reactive protein (CRP) activates macrophages to express EMMPRIN and MMP-9 in vitro and whether statins inhibit it.

Rat peritoneal macrophages were collected by peritoneal lavage, and were incubated in the presence or absence of CRP. CRP at 5 microg/ml increased the gene expression of EMMPRIN relative to GAPDH, measured by RT-PCR, by 1.67+/-0.07 fold at 24 h and by 1.85+/-0.49 fold at 48 h (both p<0.05). The gene expression of MMP-9 in the presence of CRP at 5 microg/ml was followed by 1.36+/-0.11 fold increase at 24 h and by 3.95+/-0.81 fold at 48 h (both p<0.05). CRP at 5 microg/ml for 48 h increased by 6 fold MMP-9 activity, measured by zymography, without affecting tissue inhibitor of metalloproteinases-1. Boiled CRP at 5 mug/ml for 48 h unaffected MMP-9 activity. Fluvastatin blocked the CRP-induced increases in EMMPRIN and MMP-9 expression and activity. Diphenylene iodonium, an inhibitor of NADPH oxidase, had a similar effect on MMP-9 activity. Fluvastatin suppressed the CRP-induced increases in 8-epi-prostaglandin F(2alpha) levels in the condition media.

CRP is an activator for macrophages to enhance EMMPRIN and MMP-9 expression. Fluvastatin inhibits them presumably through its antioxidant effect.

Reactive oxygen species, such as superoxide anion (O2-) and hydrogen peroxide (H2O2), may act as second messengers of intracellular signaling and play a key role in the pathogenesis of atherosclerosis. The nuclear factor kappaB (NF-kappa B) is a redox-sensitive transcription factor that is involved in this process. The aim of the present study was to investigate the molecular mechanisms of action of statins on cultured vascular smooth muscle cells (VSMC) and monocytic cells (THP-1) under oxidative stress. In THP-1 and cultured VSMC, O2- caused an increase in NF-kappa B activation (P < 0.05) that was correlated with inhibitory I kappa B-alpha degradation. Atorvastatin or simvastatin decreased NF-kappa B activation induced by oxidative stress by around 50% in both cell types and was correlated with the I kappa B-alpha levels. In monocytes, O2- increased I kappa B kinase (IKK)-1 and IKK-2 activity (P < 0.05) and p38 and p42/44 activation and phosphorylation, which was reduced by statins. PD 98059 (p42/44 inhibitor) and SB20358 (p38 inhibitor) decreased NF-kappa B binding activity and prevented I kappa B-alpha degradation. However, we only observed a reduction in IKK-1 and IKK-2 activity with PD98059. Statins diminish NF-kappa B activation elicited by oxidative stress through the inhibition of IKK-1/-2, p38, and p42/44 activation. These data may help to further understand the molecular mechanisms of statins in cardiovascular disease.

Patients with chronic pancreatitis (CP) are at high risk of antioxidant deficiencies. Furthermore, this disease can lead to diabetes mellitus (DM) that could exacerbate the severity of oxidative stress. Oxidative stress and the resulting LDL oxidation are a major cause of atherosclerosis.

The objective of the study was to ascertain whether diabetes significantly modifies oxidative status in patients with CP.

CP patients with or without DM were compared with type 1 DM patients and healthy control subjects.

Two-way factorial analyses showed that a decrease in the plasma concentrations of vitamin A, vitamin E, and carotenoids accompanied both CP and DM, and CP was also associated with lower plasma concentrations of selenium and zinc, lower catalase activity, and higher plasma concentrations of copper. The lag phase of LDL oxidation was lower in CP patients with or without DM than in the control subjects, whereas there was no significant difference between type 1 DM patients and control subjects. Multivariate analysis showed that LDL vitamin E (R2 = 0.24, P < 0.0001) and fasting plasma glucose (R2 = 0.32, P < 0.0001) concentrations were the main determinants of the lag phase of LDL oxidation.

Antioxidant status is altered in CP patients, particularly in those who also have DM. In these patients, a vitamin E deficiency and an elevated plasma glucose concentration were associated with significantly higher LDL oxidizability.

Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia.

In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction.

Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.

Long- and short-term trials with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated significant reductions in cardiovascular events in patients with and without history of coronary heart disease. Statins are well-established low-density lipoprotein (LDL)-lowering agents, but their clinical benefit is believed to result from a number of lipid and non-lipid effects beyond LDL lowering, including a rise in plasma high-density lipoprotein levels. Beyond improving the lipid profile, statins have additional non-lipid effects including benefit on endothelial function, inflammatory mediators, intima-media thickening, prothombotic factors that ultimately result in plaque stabilization. These effects arise through the inhibition of several mevalonate-derived metabolites other than cholesterol itself, which are involved in the control of different cellular functions. Although statins represent the gold standard in the prevention and treatment of coronary heart disease, combination therapy with other lipid-lowering drugs, as well as novel therapeutic indications, may increase their therapeutic potential.

Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The C-reactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

To review relevant literature and provide an opinion on the class effect of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins).

Primary and review articles were identified by MEDLINE search (1990-July 2002).

Editorials, studies, and review articles related to the class effect or therapeutic interchangeability of statins were reviewed. Also included was information that is relevant to this topic.

Although statins share common main actions, they may have clinically important differences in terms of efficacy and safety. At fixed or allowable dosages, rosuvastatin, atorvastatin, and simvastatin produced greater low-density lipoprotein cholesterol-lowering effects compared with other statins. Some statins have shown reduction in either cardiovascular and/or total mortality. Statins also differ in their structure, pharmacokinetics, potency, and rate of metabolism, any or all of which may have clinical significance. Although inconclusive, subtle differences in nonlipid effects of some statins may have contributed to positive benefits observed in clinical studies. As a result of drug-related deaths, cerivastatin was withdrawn voluntarily from the market, which may raise the question whether there is therapeutic interchangeability (due to class effect) among statins.

Despite the competition for market share and strategies attempting to identify differences in therapeutic value, few head-to-head comparisons between statins have been performed. The limited, available data suggest that statins are not therapeutically interchangeable.

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has recently been reported to have the antioxidative activity in vitro. However, it is still unclear whether chronic treatment with this drug actually leads to amelioration of the redox status in the body. In this study, we investigated the antioxidative effect of fluvastatin in vivo, using a vitamin E-deficient hamster model, an in vivo model of enhanced oxidative stress. After pre-treatment with a vitamin E-deficient diet for 2 months, fluvastatin, pravastatin or probucol was added to the diet for 1 month. Vitamin E deficiency caused a significant increase in the levels of plasma oxidative stress markers such as 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and hydroperoxides. Furthermore, there was a significant increase in the oxidizability of plasma lipids in the vitamin E-deficient animals, indicating that the oxidative stress was increased in the circulation. Fluvastatin markedly depressed the above oxidative stress markers in plasma, and significantly decreased the oxidizability of plasma lipids without affecting their levels. Probucol, a reference antioxidant, also showed a similar effect while pravastatin, another HMG-CoA reductase inhibitor, showed only a weak improvement. We suggest that the treatment with fluvastatin leads to a reduction of oxidative stress in vivo, which is mainly derived from its antioxidative property rather than its lipid-lowering activity.