cerivastatin and Disease-Models--Animal

Cerivastatin is an HMG-CoA reductase inhibitor used for the treatment of patients with hypercholesterolaemia. The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised clinical trials. Earlier studies used cerivastatin at relatively low dosages of < or =0.3mg orally once daily, but more recent studies have focused on dosages of 0.4 or 0.8 mg/day currently recommended by the US Food and Drug Administration (FDA). Along with modest improvements in serum levels of triglycerides and high density lipoprotein (HDL)-cholesterol, cerivastatin 0.4 to 0.8 mg/day achieved marked reductions in serum levels of low density lipoprotein (LDL)-cholesterol (33.4 to 44.0%) and total cholesterol (23.0 to 30.8%). These ranges included results of a pivotal North American trial in almost 1000 patients with hypercholesterolaemia. In this 8-week study, US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol were achieved in 84% of patients randomised to receive cerivastatin 0.8 mg/day, 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for starting pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. In 90% of all patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). Various subanalyses of clinical trials with cerivastatin indicate that the greatest lipid-lowering response can be expected in women and elderly patients. Cerivastatin is generally well tolerated and adverse events have usually been mild and transient. The overall incidence and nature of adverse events reported with cerivastatin in clinical trials was similar to that of placebo. The most frequent adverse events associated with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis. In the large pivotal trial, significant elevations in serum levels of creatine kinase and transaminases were reported in a small proportion of patients receiving cerivastatin but not in placebo recipients. As with other HMG-CoA reductase inhibitors, rare reports of myopathy and rhabdomyolysis have occurred with cerivastatin, although gemfibrozil or cyclosporin were administered concomitantly in most cases. Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary. Cerivastatin is a well tolerated and effective lipid-lowering agent for patients with hypercholesterolaemia. When given at dosages currently recommended by the FDA in the US, cerivastatin achieves marked reductions in serum levels of LDL-cholesterol, reaching NCEP target levels in the vast majority of patients. Thus, cerivastatin provides a useful (and potentially cost effective) alternative to other currently available HMG-CoA reductase inhibitors as a first-line agent for hypercholesterolaemia.

Topics: Administration, Oral; Adult; Aged; Arteriosclerosis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Male; Middle Aged; Pyridines

Previously, we have demonstrated the potential of plasma 2-hydroxyglutarate (2HG) as an easily detectable biomarker for skeletal muscle injury in rats. Here, we examined whether plasma 2HG was superior to conventional skeletal muscle damage biomarkers, including aspartate aminotransferase (AST), creatine kinase (CK), and skeletal muscle-type CK isoenzyme (CK-MM) levels, in rats. Skeletal muscle injury was induced in 4- or 9-week-old male Fischer 344 rats by cerivastatin (CER) or tetramethyl-p-phenylenediamine (TMPD) administration. Plasma 2HG levels were measured on days 4, 8, and 11 (CER group) and at 6 and 24 hr post-administration (TMPD group). Plasma AST, CK, and CK-MM activities and histopathological changes in the rectus femoris muscle were evaluated at the study endpoints. In the CER group, AST, CK, and CK-MM increased in 4- and 9-week-old rats, whereas increases in CK (4- and 9-week-old rats) and CK-MM (4-week-old rats) were not obvious in the TMPD group. In both 4- and 9-week-old rats, plasma 2HG increased on day 8 and at 24 hr post-administration in the CER and TMPD groups, respectively. Histopathological analysis revealed myofiber vacuolation and necrosis in both groups. The histopathological damage to the rectus femoris muscle was more severe in the CER than in the TMPD group. Increased plasma 2HG was associated with CER- and TMPD-induced skeletal muscle injuries in rats and was not affected by age differences or repeated blood collection. The results suggest that plasma 2HG is superior to CK and CK-MM as a biomarker for mild skeletal muscle injury.

Topics: Aniline Compounds; Animals; Biomarkers; Disease Models, Animal; Glutarates; Male; Muscle, Skeletal; Myofibrils; Necrosis; Pyridines; Quadriceps Muscle; Rats, Inbred F344; Time Factors; Vacuoles

To identify new candidate biomarkers for skeletal muscle toxicity, an unbiased metabolomic analysis was performed in rats treated with two distinct myotoxicants, cerivastatin (CER) and tetramethyl-p-phenylenediamine (TMPD). Skeletal muscle toxicity was induced in male Fischer 344 rats by administering CER or TMPD and monitored using established endpoints, such as increased plasma creatine kinase (CK) activity and histopathology, and a metabolomic analysis of skeletal muscle and plasma samples. Plasma CK levels in CER-treated rats were markedly elevated at Day 11; however, those in TMPD-treated rats showed a statistically significant decrease at 24 hr after dosing. Light microscopy revealed that vacuolated or necrotic fibers were evident in all CER-treated rats on Day 11, and slightly vacuolated fibers were observed in TMPD-treated rats at 6 and 24 hr after dosing. Metabolomic analysis of the rectus femoris indicated increases in 2-hydroxyglutarate (2HG) in CER-treated rats and hexanoylcarnitine in CER- and TMPD-treated rats. There were also increases in plasma 2HG in CER-treated rats on Days 8 and 11 and in TMPD-treated rats at 24 hr after dosing and increases in plasma hexanoylcarnitine in CER-treated rats on Day 11 and in TMPD-treated rats at 6 and 24 hr after dosing. These experiments demonstrated the potential of plasma 2HG and hexanoylcarnitine as specific and easily detectable biomarkers for skeletal muscle toxicity in rats and demonstrated the value of metabolomics for biomarker detection and identification in toxicological studies.

Topics: Aniline Compounds; Animals; Biomarkers; Carnitine; Creatine Kinase; Disease Models, Animal; Glutarates; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Diseases; Pyridines; Rats, Inbred F344

Rare instances of myopathy are associated with all statins, but cerivastatin was withdrawn from clinical use due to a greater incidence of myopathy. The mechanism of statin-induced myopathy with respect to tissue disposition was investigated by measuring the systemic, hepatic, and skeletal muscle exposure of cerivastatin, rosuvastatin, and simvastatin in rats before and after muscle damage. The development of myopathy was not associated with the accumulation of statins in skeletal muscle. For each statin exposure was equivalent in muscles irrespective of their fibre-type sensitivity to myopathy. The low amount of each statin in skeletal muscle relative to the liver does not support a significant role for transporters in the disposition of statins in skeletal muscle. Finally, the concentration of cerivastatin necessary to cause necrosis in skeletal muscle was considerably lower than rosuvastatin or simvastatin, supporting the concept cerivastatin is intrinsically more myotoxic than other statins.

Topics: Animals; Disease Models, Animal; Female; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Muscle, Skeletal; Muscular Diseases; Pyridines; Pyrimidines; Rats; Rats, Wistar; Rosuvastatin Calcium; Simvastatin; Sulfonamides

4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.

Topics: Animals; Atorvastatin; Combinatorial Chemistry Techniques; Disease Models, Animal; Fluorobenzenes; Hepatocytes; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Molecular Structure; Muscle Cells; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Sulfonamides

Death attributable to septic shock syndrome depends highly on the inflammatory response and cytokine production. Inhibition of inflammation is one of the many pleiotropic effects of statins. The aim of this study was to test the hypothesis that statins have a role in altering the host response to bacterial infections and thus would prove beneficial in the prevention of microbial sepsis.. Male C57BL/6 and C3H/HeN mice received cerivastatin (4 mg/kg) or phosphate-buffered saline (PBS) intraperitoneally (i.p.), 24 and 1 h before and 24, 48, and 72 h after bacterial challenges. Sepsis was induced by i.p. injection of lipopolysaccharide (LPS) (45 mg/kg), Staphylococcus aureus (5 x 10(7) colony-forming units [CFU]/mouse), or Salmonella typhimurium (2.5 x 10(6) CFU/mouse).. Administration of cerivastatin improved significantly the survival rate of mice challenged with LPS (31% vs. 19% in the PBS group; p = 0.001), S. aureus (56% vs. 20% in PBS group; p = 0.01), or S. typhimurium (48% vs. 10% in PBS group; p = 0.03). Significantly reduced release of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 was evident in cerivastatin-treated mice after LPS challenge. Cerivastatin-treated mice showed insignificant reductions in serum TNF-alpha and IL-6 concentrations after bacterial challenge. However, significantly accelerated bacterial clearance was demonstrated in cerivastatin-treated mice 24 h after S. typhimurium infection and 48 h after S. aureus infection.. Cerivastatin protects mice against LPS- and live bacteria-induced death, an effect associated with cerivastatin-attenuated pro-inflammatory cytokine production and enhanced bacterial clearance. Hence, application of statins in the clinical setting may prove beneficial in prevention of LPS or bacterial infection-related sepsis.

Topics: Animals; Disease Models, Animal; Escherichia coli; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Lipopolysaccharides; Male; Mice; Pyridines; Salmonella typhi; Shock, Septic; Staphylococcus aureus; Tumor Necrosis Factor-alpha

Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia in a porcine coronary model.. Pigs were randomized into groups in which the coronary arteries (9 pigs, 18 coronaries in each group) had either a cerivastatin-eluting stent (CES) or a BMS. All animals survived without any adverse effects. Inflammatory cell infiltration evaluated using scanning electron microscopy on day 3 after stenting was significantly decreased in the treated vessels (inflammation score: 1.15+/-0.12 vs 2.43+/-0.34, p<0.0001). At day 28, endothelial function with intracoronary infusion of bradykinin was preserved in both the CES and BMS groups. Volumetric intravascular ultrasound images revealed decreased intimal volume in the CES group (28.3+/-5.4 vs 75.9+/-4.2 mm3, p<0.0001). Histomorphometric analysis showed reduced neointimal area (1.74+/-0.45 vs 3.83+/-0.51 mm2, p<0.0001) in the CES group despite similar injury scores (1.77+/-0.30 vs 1.77+/-0.22, p=0.97).. In porcine coronary arteries CES significantly decreased neointimal hyperplasia with a decreased early inflammatory response and without endothelial dysfunction.

Topics: Angioplasty, Balloon, Coronary; Animals; Bradykinin; Chronic Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Lipids; Microscopy, Electron, Scanning; Pyridines; Swine; Tunica Intima; Vasculitis; Vasodilator Agents

Alport syndrome is caused by mutations in genes encoding for the alpha3, alpha4 or alpha5 chain of type IV collagen leading to excessive production of fibrotic tissue and end-stage renal failure. HMG-CoA-reductase-inhibitors exhibit pleiotropic effects by which they modulate the production of connective tissue. The aim of this study was to examine the anti-fibrotic effect of the HMG-CoA-reductase-inhibitor, cerivastatin, in COL4A3 knockout mice, an animal model of Alport syndrome with progressive renal fibrosis.. Forty homozygous COL4A3 knockout mice received cerivastatin, starting 28 or 49 days after birth. Mice were sacrificed at day 52 or 66 after birth. Immunohistochemistry against laminin and fibronectin was performed. Inflammatory cell infiltration was determined by F4/80- and CD3-staining. Myofibroblasts were identified by an alpha-smooth muscle actin staining. Expression of the profibrotic cytokines, TGF-beta1 and CTGF, were determined by immunoblot.. The lifespan of treated COL4A3 knockout mice was increased by 28% compared with untreated animals (71+/-6 vs 91+/-9 days, P<0.01). Early cerivastatin treatment reduced cholesterol levels (113+/-13 vs 141+/-19 mmol/l in untreated animals, P<0.05) and serum urea (164 vs 235 mmol/l, day 66, P<0.05). Treatment also decreased proteinuria (5.5 vs 12 g/l at day 66, P<0.05). Deposition of laminin and fibronectin, expression of TGF-beta and CTGF was reduced. Infiltration of T-cells and macrophages as well as myofibroblasts appeared to be reduced in kidneys from cerivastatin-treated mice.. Cerivastatin prolongs the lifespan of COL4A3 knockout mice, reduces proteinuria and delays uraemia. These effects are associated with decreased renal fibrosis and a reduction of inflammatory cell infiltration.

Topics: Animals; Autoantigens; Cholesterol; Collagen Type IV; Disease Models, Animal; Disease Progression; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Mice; Mice, Knockout; Nephritis, Hereditary; Proteinuria; Pyridines; Transforming Growth Factor beta1; Uremia

Statins potently inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, blocking downstream biosynthesis of isoprenoid lipids and causing inhibition of protein prenylation. Prenylated signaling molecules are essential for osteoclast function, consistent with our previous observation that mevastatin can inhibit osteoclast activity in vitro. Several reports suggest that statins may also have an anabolic effect on bone and stimulate osteoblast differentiation. This study sought to determine the effects of both hydrophobic and hydrophilic statins, particularly rosuvastatin (RSV), on osteoclast function in vitro and in vivo. All statins tested (RSV, pravastatin [PRA], cerivastatin [CER], and simvastatin [SIM]) caused accumulation of unprenylated Rap-1A in rabbit osteoclast-like cells and J774 macrophages in vitro and inhibited osteoclast-mediated resorption. The order of potency for inhibiting prenylation in vitro (at concentrations of 0.01-50 muM) was CER>SIM>RSV>PRA. The most potent hydrophilic statin (CER, 0.05 and 0.3 mg/kg) inhibited prenylation in rabbit osteoclasts 24 hours after a single subcutaneous (s.c.) injection more effectively than the most potent hydrophobic statin (RSV, 20 mg/kg). However, in a mouse model of osteoporosis, s.c. 0.05 mg/kg/day CER and 2 or 20 mg/kg/day RSV for 3 weeks only mildly prevented loss of cortical and trabecular bone induced by ovariectomy. No increase in bone formation rate was observed with statin treatment, suggesting that this effect was due to inhibition of osteoclast-mediated resorption rather than increased bone formation.

Topics: Anabolic Agents; Animals; Animals, Newborn; Bone and Bones; Bone Resorption; Cells, Cultured; Disease Models, Animal; Female; Hydrophobic and Hydrophilic Interactions; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred BALB C; Osteoclasts; Osteoporosis; Ovariectomy; Pravastatin; Protein Prenylation; Pyridines; Rabbits; rap1 GTP-Binding Proteins; Signal Transduction; Simvastatin; Water

A mutation of the CD36 gene that encodes a fatty acid transporter has been reported to play a role in insulin resistance in spontaneously hypertensive rat (SHR). Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study was to determine the role of CD36 and the significance of statin therapy in insulin-resistance syndromes. We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARgamma. The CD36 genotype and microsatellite markers on chromosome 4 were also determined. The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF rats but restored by a low dose of cerivastatin without significant changes in serum cholesterol. These relaxations were also restored by a high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased the aortic expression of CD36 and PPARgamma mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF rats, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats. In conclusion, insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have pronounced beneficial effects in insulin-resistance syndromes.

Topics: Animals; Aorta; CD36 Antigens; Diabetes Mellitus; Disease Models, Animal; Endothelium, Vascular; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Insulin Resistance; Male; Microsatellite Repeats; PPAR gamma; Pyridines; Rats; Rats, Inbred OLETF; RNA, Messenger

We investigated the effect of cerivastatin, a statin, on the development of diabetic nephropathy in spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes.. Diabetic SHR were given standard chow or chow containing cerivastatin at a dose of 0.1 mg/kg or 1.0 mg/kg for 12 weeks. Effects of cerivastatin on urinary albumin excretion, mesangial expansion, glomerular macrophage infiltration, and the number of anionic sites on the glomerular basement membrane (GBM) were assessed.. Cerivastatin did not affect the blood glucose concentration, blood pressure or serum cholesterol concentration in diabetic SHR. However, cerivastatin treatment caused a dose-dependent decrease of albuminuria and hyperfiltration. At 1.0 mg/kg, cerivastatin inhibited the diabetes-induced expansion of mesangial and tuft areas on histological examination of the kidneys, as well as the loss of anionic sites from the GBM evaluated with polyetyleneimine and the intraglomerular infiltration of ED1-positive macrophages evaluated by immunohistochemistry. Whole-kidney expression of mRNA for MCP-1 and TGF-beta, estimated by the real-time quantitative RT-PCR, was increased (both 2.6-fold) in untreated diabetic SHR at 12 weeks. Cerivastatin treatment (1.0 mg/kg) inhibited the up-regulated expression of MCP-1 and TGF-beta mRNA (decreased to 48% and 34%, respectively) in diabetic SHR.. In this hypertensive model of diabetic nephropathy, cerivastatin decreased albuminuria through suppression of glomerular hyperfiltration, mesangial expansion, and the loss of charge barrier independently of a cholesterol-lowering effect. These preventive effects could be at least partly due to inhibition of macrophage recruitment and activation, and inhibition of TGF-beta overexpression.

Topics: Animals; Base Sequence; Chemokine CCL2; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; DNA Primers; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Glomerulus; Macrophages; Male; Pyridines; Rats; Rats, Inbred SHR; Stereoisomerism; Transforming Growth Factor beta

The aim of this study was to test the feasibility of cine magnetic resonance imaging (MRI) for assessment of the infarcted rat and mouse heart and to compare the results with established methods. These models have been proven to predict genesis and prevention of heart failure in patients. The value of cine MRI was tested in studies investigating interventions to change the course of the remodeling process. MRI was performed for determination of left ventricular (LV) volumes and mass, myocardial infarct (MI) size and cardiac output. LV wet weight was determined after MRI. Rats underwent conventional hemodynamic measurements for determination of cardiac output and LV volumes by electromagnetic flowmeter and pressure-volume curves. Infarct size was determined by histology. MRI-acquired MI-size (18.5+/-2%) was smaller than that found by histology (22.8+/-2.5%, p<0.05) with close correlation (r=0.97). There was agreement in LV mass between MRI and wet weight (r=0.97, p<0.05) and in the MRI- and flowmeter measurements of cardiac output (r=0.80, p<0.05). Volume by MRI differed from pressure-volume curves with good correlation (r=0.96, p<0.05). In a serial study of mice after coronary ligation, LV hypertrophy at 8 weeks was detected (Sham 105.1+/-7.9 mg, MI 144.4+/-11.7 mg, p<0.05). Left ventricles were enlarged in infarcted mice (end-diastolic volume, week 8: Sham 63.5+/-4 microl, MI 94.2 microl, p<0.05). In conclusion, cine MRI is a valuable diagnostic tool applicable to the rat and mouse model of MI. Being non-invasive and exact it offers new insights into the remodeling process after MI because serial measurements are possible. The technique was applied to study several interventions and proved its usefulness.

Topics: Animals; Cardiac Output; Disease Models, Animal; Heart Failure; Heart Ventricles; Humans; Ischemia; Magnetic Resonance Imaging, Cine; Mice; Myocardial Infarction; Myocardial Ischemia; Pyridines; Rats; Reproducibility of Results; Sensitivity and Specificity; Species Specificity; Statistics as Topic; Stroke Volume; Testosterone; Ventricular Dysfunction, Left; Ventricular Remodeling

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Ischemia; Kidney Glomerulus; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pyridines; Rats; Rats, Sprague-Dawley

We sought to assess the influence of long-term hydroxymethylglutaryl coenzyme A reductase inhibition (statin) therapy on left ventricular (LV) remodeling after myocardial infarction (MI) by use of serial cardiac magnetic resonance imaging (CMRI) studies.. Statin therapy has been shown to reduce cardiac hypertrophy in vitro and in vivo, but the influence on LV post-MI remodeling is largely unknown.. The CMRI measurements were taken four and 12 weeks after left coronary artery ligation in a 7.05-tesla Biospec. The MI size, LV mass and volumes, cardiac output (CO), and ejection fraction were determined. Rats were treated for 12 weeks with either placebo (P), cerivastatin (C; 0.6 mg/kg body weight per day) as a dietary supplement, or cerivastatin plus the nitric oxide synthase (NOS) inhibitor N-methyl-L-arginine methyl ester (L-NAME, 76 mg/100 ml) and hydralazine (8 mg/100 ml) in drinking water (CLH) to assess the contribution of endogenous nitric oxide formation.. Administration of cerivastatin attenuated hypertrophy after MI, and this effect was completely abolished by NOS inhibition (increase of LV mass from 4 to 12 weeks after MI: 235.3 +/- 33.7 mg with P vs. 59.8 +/- 20.5 mg with C vs. 239.5 +/- 16.0 mg with CLH; p < 0.05 vs. P and CLH). Left ventricular dilation was not changed (increase of end-diastolic volume from 4 to 12 weeks after MI: 108.7 +/- 28.8 with P vs. 126.6 +/- 20.5 with C vs. 173.7 +/- 25.1 with CLH; p = NS). The CO was higher in the cerivastatin group (12 weeks: 76.1 +/- 2.9 ml/min with P vs. 95.8 +/- 4.8 ml/min with C; p < 0.05). The effects of cerivastatin were abolished by NOS inhibition in the CLH group (CO at 12 weeks: 69.3 +/- 2.8 ml/min, p < 0.05 vs. C).. Left ventricular remodeling was profoundly changed by statin treatment. Hypertrophy was attenuated, and global function was improved. These positive effects were abolished by NOS inhibition.

Topics: Animals; Disease Models, Animal; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Male; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyridines; Rats; Rats, Wistar; Ventricular Function, Left; Ventricular Remodeling

The development of atherosclerotic cardiovascular complications caused by hyperlipidemia is a common and serious problem for long-term survivors of organ transplantation. However, adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and lymphocyte function-associated antigen (LFA)-1 are involved in allograft rejection, possibly by providing costimulatory signals. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin has been shown to suppress ICAM-1 expression in acute inflammatory responses.. In this study, we evaluated the immunosuppressive effects of cerivastatin in rat cardiac allografts. The hearts of Fischer rats were transplanted heterotopically into Lewis rats. Cerivastatin (2 mg/kg) was administrated intraperitoneally to recipients for 7 consecutive days from the day before transplantation.. Graft survival in the cerivastatin-treated group (n = 8) was significantly longer than in controls (n = 10) (24.6 +/- 2.2 days vs 10.2 +/- 1.3 days, p < 0.05). Mixed lymphocyte reaction (MLR) showed that on Day 8 after grafting, the proliferative response of alloreactive T cells against F344 alloantigen in cerivastatin-treated rats was significantly more suppressed than in Lewis rats. The Interleukin-2 concentration of supernatant in MLR cultures in the cerivastatin-treated group was lower than in the control group. Immunohistochemical analysis showed that the percentage of CD4-positive cells to infiltrating mononuclear cells was less prominent in the cerivastatin-treated group (9.8% +/- 2.2%) than in the control group (20.9% +/- 3.2%).. The HMG-CoA reductase inhibitor cerivastatin effectively suppressed acute graft rejection, possibly by blocking intercellular signals via ICAM/LFA-1, and cerivastatin may be a candidate for treating patients with hyperlipidemia who undergo organ transplantation.

Topics: Animals; Disease Models, Animal; Graft Survival; Heart Transplantation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune Tolerance; Immunohistochemistry; Intercellular Adhesion Molecule-1; Interleukin-2; Leukocytes; Lymphocyte Culture Test, Mixed; Lymphocyte Function-Associated Antigen-1; Male; Models, Cardiovascular; Pyridines; Rats; Rats, Inbred F344; Rats, Inbred Lew; Signal Transduction; Treatment Outcome

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be due to their cholesterol-lowering independent effects on the blood vessels. Chronic inhibition of endothelial nitric oxide (NO) synthesis by oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation as well as subsequent arteriosclerosis. The aim of the study is to test whether treatment with statins attenuates such arteriosclerotic changes through their cholesterol-lowering independent effects. We investigated the effect of statins (pravastatin and cerivastatin) on the arteriosclerotic changes in the rat model. We found that treatment with statins did not affect serum lipid levels but markedly inhibited the L-NAME-induced vascular inflammation and arteriosclerosis. Treatment with statins augmented endothelial NO synthase activity in L-NAME-treated rats. We also found the L-NAME induced increase in Rho membrane translocation in hearts and its prevention by statins. Such vasculoprotective effects of statins were suppressed by the higher dose of L-NAME. In summary, in this study, we found that statins such as pravastatin and cerivastatin inhibited vascular inflammation and arteriosclerosis through their lipid-lowering independent actions in this model. Such antiarteriosclerotic effects may involve the increase in endothelial NO synthase activity and the inhibition of Rho activity.

Topics: Animals; Anti-Inflammatory Agents; Arteriosclerosis; Blood Pressure; Chemokine CCL2; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Lipids; Macrophages; Male; Monocytes; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitrites; Nitroarginine; Peptidyl-Dipeptidase A; Pravastatin; Proliferating Cell Nuclear Antigen; Pyridines; Rats; Rats, Inbred WKY; rhoA GTP-Binding Protein; RNA, Messenger; Systole; Transforming Growth Factor beta; Transforming Growth Factor beta1

We recently obtained evidence demonstrating that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-untranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction.. Endothelium-dependent relaxation to acetylcholine and the calcium ionophore A23187 was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with cerivastatin (0.1 mg. kg body wt(-1). d(-1)) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-kDa cytosolic protein and reduced stability of eNOS mRNA. Cerivastatin treatment upregulated eNOS expression and reduced the interaction of the cytosolic protein with the 3'-untranslated region of eNOS mRNA. Mononuclear cells from hypercholesterolemic rabbits also showed a marked reduction of eNOS expression and eNOS mRNA stability and an increase in binding activity of the cytosolic protein, which were also prevented by cerivastatin treatment.. These results demonstrate the presence of a 60-kDa protein that binds to eNOS mRNA and reductions in eNOS expression in both vascular wall and mononuclear cells that are prevented by cerivastatin.

Topics: 3' Untranslated Regions; Animals; Aorta; Cytosol; Disease Models, Animal; Endothelium, Vascular; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; In Vitro Techniques; Ionophores; Leukocytes, Mononuclear; Macromolecular Substances; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Binding; Pyridines; Rabbits; RNA Stability; RNA, Messenger; Substrate Specificity; Vasodilation; Vasodilator Agents

Statins are effective in prevention of end-organ damage; however, the benefits cannot be fully explained on the basis of cholesterol reduction. We used an angiotensin II (Ang II)-dependent model to test the hypothesis that cerivastatin prevents leukocyte adhesion and infiltration, induction of inducible nitric oxide synthase (iNOS), and ameliorates end-organ damage.. We analyzed intracellular targets, such as mitogen-activated protein kinase and transcription factor (nuclear factor-kappaB and activator protein-1) activation. We used immunohistochemistry, immunocytochemistry, electrophoretic mobility shift assays, and enzyme-linked immunosorbent assay techniques. We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from week 4 to 7 with cerivastatin (0.5 mg/kg by gavage).. Untreated dTGR developed hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. dTGR mortality at the age of seven weeks was 45%. Immunohistochemistry showed increased iNOS expression in the endothelium and media of small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR, which was greater in cortex than medulla. Phosphorylated extracellular signal regulated kinase (p-ERK) was increased in dTGR; nuclear factor-kappaB and activator protein-1 were both activated. Cerivastatin decreased systolic blood pressure compared with untreated dTGR (147 +/- 14 vs. 201 +/- 6 mm Hg, P < 0.001). Albuminuria was reduced by 60% (P = 0.001), and creatinine was lowered (0.45 +/- 0.01 vs. 0.68 +/- 0.05 mg/dL, P = 0. 003); however, cholesterol was not reduced. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression was diminished, while neutrophil and monocyte infiltration in the kidney was markedly reduced. ERK phosphorylation and transcription factor activation were reduced. In addition, in vitro incubation of vascular smooth muscle cells with cerivastatin (0.5 micromol/L) almost completely prevented the Ang II-induced ERK phosphorylation.. Cerivastatin reduced inflammation, cell proliferation, and iNOS induction, which led to a reduction in cellular damage. Our findings suggest that 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibition ameliorates Ang II-induced end-organ damage. We suggest that these effects were independent of cholesterol.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cell Division; Cholesterol; Creatinine; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Kidney; Kidney Failure, Chronic; Leukocytes; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Organ Size; Phosphorylation; Plasminogen Activators; Pyridines; Rats; Rats, Sprague-Dawley; Renin; Thromboplastin; Transcription Factor AP-1; Urea; Vascular Cell Adhesion Molecule-1; Vasoconstrictor Agents