pitavastatin and Disease-Models--Animal

The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells.. In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II-induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II-induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol.. These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Atorvastatin; Biomarkers; Cardiomegaly; Cells, Cultured; Cholesterol; Cholesterol, LDL; Coronary Vessels; Cross-Over Studies; Cytoskeletal Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Guanine Nucleotide Exchange Factors; Heptanoic Acids; Human Umbilical Vein Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Mice; Mice, Knockout; Neuropeptides; Oxidative Stress; Phosphatidylinositol 3-Kinase; Pravastatin; Proto-Oncogene Proteins c-akt; Pyrroles; Quinolines; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; RNA Interference; Signal Transduction; Transfection

Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model.. To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples.. Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs.. The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

Topics: Animal Fins; Animals; Animals, Genetically Modified; Benzhydryl Compounds; Benzoxazoles; Butyrates; Diet, High-Fat; Disease Models, Animal; Exome Sequencing; Gene Ontology; Glucosides; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Non-alcoholic Fatty Liver Disease; Oryzias; PPAR alpha; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Glucose Transporter 2 Inhibitors; Transcriptome

Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. Ex vivo molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation.. These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Chemokine CCL2; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Macrophages; Male; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Monocytes; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Quinolines

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Inflammation Mediators; Lymph Nodes; Male; Mevalonic Acid; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Quinolines; Spinal Cord; T-Lymphocytes, Regulatory; Th17 Cells

Topics: Animals; Anti-Inflammatory Agents; Cyclosporine; Disease Models, Animal; Drug Carriers; Drug Combinations; Drug Compounding; Inflammation Mediators; Interleukin-1beta; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nanoparticles; NLR Family, Pyrin Domain-Containing 3 Protein; Peptidyl-Prolyl Isomerase F; Polylactic Acid-Polyglycolic Acid Copolymer; Quinolines; Receptors, CCR2; Time Factors

Ginkgo biloba L. is a traditional Chinese medicine for hyper lipaemia. Ginkgo flavonols and terpene lactones are responsible for the lipid-lowering effect in non-alcoholic fatty liver disease (NAFLD). However, the pharmacokinetics of ginkgo flavonols and terpene lactones in NAFLD was not clarified.. To investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats.. Male rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of. The plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6-32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2-3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the C. NAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.

Topics: Animals; Area Under Curve; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Ginkgo biloba; HEK293 Cells; Herb-Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Male; Non-alcoholic Fatty Liver Disease; Plant Extracts; Quinolines; Rats; Rats, Sprague-Dawley; Solute Carrier Organic Anion Transporter Family Member 1B3

Statins are widely used for the treatment of atherosclerotic cardiovascular diseases. They inhibit cholesterol biosynthesis in the liver and cause pleiotropic effects, including anti-inflammatory and antioxidant effects. To develop novel therapeutic drugs, the effect of blood-borne lipid molecules on the pleiotropic effects of statins must be elucidated. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for hypercholesterolemia, are suitable for the determination of lipid molecules in the blood in response to statins because their lipoprotein metabolism is similar to that of humans. Herein, lipid molecules were investigated by lipidome analysis in response to pitavastatin using WHHLMI rabbits. Various lipid molecules in the blood were measured using a supercritical fluid chromatography triple quadrupole mass spectrometry. Cholesterol and cholesterol ester blood concentrations decreased by reducing the secretion of very low density lipoproteins from the liver. Independent of the inhibition effects of cholesterol biosynthesis, the concentrations of some lipids with anti-inflammation and antioxidant effects (phospholipid molecules with

Topics: Animals; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Lipoproteins; Quinolines; Rabbits

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Autophagy; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Humans; Mice; Neurofibrillary Tangles; Phosphorylation; Proteasome Endopeptidase Complex; Proteolysis; Quinolines; rho-Associated Kinases; Signal Transduction; tau Proteins; Tauopathies

Aortic dissection is a life-threatening disease. At present, the only therapeutic strategies available are surgery and antihypertensive drugs. Moreover, the molecular mechanisms underlying the onset of aortic dissection are still unclear. We established a novel aortic dissection model in mice using pharmacologically induced endothelial dysfunction. We then used the Japanese Adverse Drug Event Report database to investigate the role of pitavastatin in preventing the onset of aortic dissection.. To induce endothelial dysfunction, Nω-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, was administered to C57BL/6 mice. Three weeks later, angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, were administered with osmotic mini-pumps. False lumen formation was used as the pathological determinant of aortic dissection. The incidences of aortic dissection and death from aneurysmal rupture were significantly higher in the Nω-nitro-L-arginine methyl ester, Ang II, and BAPN (LAB) group than they were in the Ang II and BAPN (AB) group.Pitavastatin was administered orally to LAB mice. It significantly lowered the incidences of dissection and rupture. It also decreased inflammation and medial degradation, both of which were exacerbated in the LAB group. The Japanese Adverse Drug Event Report database analysis indicated that there were 113 cases of aortic dissection out of 95 090 patients (0.12%) not receiving statins but only six cases out of 16 668 patients receiving statins (0.04%) (odds ratio: 0.30; P = 0.0043).. Our results suggest that endothelial dysfunction is associated with the onset of aortic dissection and pitavastatin can help prevent this condition.

Topics: Animals; Aortic Dissection; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred C57BL; Quinolines

Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system.. Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting.. PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains.. PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.

Topics: Albuminuria; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Phosphorylation; Quinolines; Rats, Inbred SHR; Rats, Inbred WKY; Up-Regulation

Blood-brain barrier (BBB) disruptions are a key feature of hyperglycemia (HG)-induced cerebral damage. Patients with diabetes mellitus often have other cerebrovascular disease risk factors including hypertension, dyslipidemia, arrhythmia, and atherosclerosis obliterans. However, whether the drugs for these comorbidities are effective for improving HG-induced BBB damage is unclear.. We investigated the effect of pitavastatin, candesartan, cilostazol, propranolol, and eicosapentaenoic acid on HG-induced BBB damage. In vitro BBB models consisting of primary cultures of rat brain capillary endothelial cells were subjected to HG (55 mM d-glucose).. We observed a significant decrease in transendothelial electrical resistance (TEER) with HG, showing that HG compromised the integrity of the in vitro BBB model. No significant decrease in cell viability was seen with HG, but HG increased the production of reactive oxygen species. Pitavastatin and candesartan inhibited decreases in TEER induced by HG.. In summary, pitavastatin and candesartan improved HG-induced BBB damage and this in vitro model of HG-induced BBB dysfunction contributes to the search for BBB protective drugs.

Topics: Animals; Benzimidazoles; Biphenyl Compounds; Blood-Brain Barrier; Cilostazol; Disease Models, Animal; Eicosapentaenoic Acid; Electric Impedance; Hyperglycemia; Propranolol; Quinolines; Rats; Rats, Wistar; Reactive Oxygen Species; Tetrazoles

Topics: Animals; Disease Models, Animal; Drug Delivery Systems; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Injections, Intravenous; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Myocardial Infarction; Nanoparticles; Quinolines; Ventricular Remodeling

Topics: Animals; Cells, Cultured; Disease Models, Animal; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Monocyte-Macrophage Precursor Cells; Myocardial Infarction; Nanotechnology; Neovascularization, Physiologic; Prognosis; Quinolines; Risk Factors; Treatment Outcome; Wound Healing

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-A) reductase, and studies have shown that statins also have anti-inflammatory and immunomodulatory properties. The purpose of this study was to investigate the anti-asthmatic effects of pitavastatin, a type of statin, in an asthma mouse model. Mice were sensitized and challenged with ovalbumin (OVA) to establish the asthma model. These mice were then treated with inhaled pitavastatin (5 mg/kg) or dexamethasone (2 mg/kg), the latter of which served as a positive control. The results of the study showed that pitavastatin reduced allergen-induced increases in airway resistance and alleviated bronchial tube thickness and goblet cell hyperplasia in lung tissues. In addition, the results showed that pitavastatin inhibited OVA-induced increases in eosinophil counts and total inflammatory cell counts in bronchoalveolar lavage fluid (BALF) and increased the percentage of CD4+ CD25+ Foxp3+ Treg in the BALF of asthmatic mice. IL-4 and IL-17 levels were decreased, whereas IFN-γ levels were significantly increased in the BALF of pitavastatin-treated mice compared with the BALF of OVA-challenged mice. These results suggest that pitavastatin has potential as a therapy for allergic airway disease and that its effects are associated with its ability to regulate CD4+ CD25+ Foxp3+ T cell counts.

Topics: Administration, Inhalation; Aerosols; Airway Resistance; Animals; Anti-Asthmatic Agents; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Forkhead Transcription Factors; Gene Expression; Inflammation Mediators; Lymphocyte Count; Mice; Quinolines; Respiratory Hypersensitivity; T-Lymphocytes, Regulatory

This study was carried out to evaluate the effect of intranasal pitavastatin (PVS) on pentylenetetrazole (PTZ)-induced seizures, increasing current electroshock (ICES) seizures, and status epilepticus in mice. Intranasal PVS, 0.5 and 1.0mg/kg, showed significant increase in latency to PTZ-induced seizures and ICES seizure threshold compared to control; however, the effects were dose-dependent and were more significant at higher dose. Further, intranasal PVS (1.0mg/kg) but not intravenous PVS (50.0mg/kg) showed effective protection against PTZ-induced status epilepticus. No impairment in cognitive functions was observed following intranasal PVS (1.0mg/kg), thus making it a prospective therapeutic approach for acute seizures and status epilepticus.

Topics: Administration, Intranasal; Animals; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Neuroprotective Agents; Prospective Studies; Quinolines; Seizures; Status Epilepticus

Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions.. We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability.. We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions.. Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.

Topics: Angiopoietin-Like Protein 1; Animals; Capillary Permeability; Disease Models, Animal; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Pulmonary Emphysema; Quinolines; Smoking; Tight Junction Proteins; Tight Junctions

There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models.. Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon.. NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.

Topics: Anesthesia; Animals; Blood Pressure; Cardiotonic Agents; Cell Death; Cells, Cultured; Consciousness; Disease Models, Animal; Heart Rate; Kidney Function Tests; Lactic Acid; Liver Function Tests; Magnetic Resonance Imaging; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nanoparticles; No-Reflow Phenomenon; Phosphorylation; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Proto-Oncogene Proteins c-akt; Quinolines; Stroke Volume; Swine; Swine, Miniature; Translational Research, Biomedical; Ventricular Remodeling

There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury.. In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium.. Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

Topics: Animals; Blotting, Western; Capillary Permeability; Cardiotonic Agents; Disease Models, Animal; Drug Delivery Systems; Echocardiography; Flow Cytometry; Injections, Intravenous; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nanoparticles; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quinolines; Rats; Rats, Sprague-Dawley; Signal Transduction

Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture.. We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture.. The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model.

Topics: Adoptive Transfer; Animals; Apolipoproteins E; Brachiocephalic Trunk; Cell Movement; Chemokine CCL2; Disease Models, Animal; Drug Delivery Systems; Genetic Therapy; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Nanoparticles; Plaque, Atherosclerotic; Quinolines; Receptors, CCR2

The use of currently marketed drug-eluting stents presents safety concerns including increased late thrombosis, which is thought to result mainly from delayed endothelial healing effects (impaired re-endothelialization resulting in abnormal inflammation and fibrin deposition). We recently developed a bioabsorbable polymeric nanoparticle (NP)-eluting stent using a novel cationic electrodeposition technology. Statins are known to inhibit the proliferation of vascular smooth muscle cells (VSMC) and to promote vascular healing. We therefore hypothesized that statin-incorporated NP-eluting stents would attenuate in-stent stenosis without delayed endothelial healing effects.. Among six marketed statins, pitavastatin (Pitava) was found to have the most potent effects on VSMC proliferation and endothelial regeneration in vitro. We thus formulated a Pitava-NP-eluting stent (20µg Pitava per stent).. In a pig coronary artery model, Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as polymer-coated sirolimus-eluting stents (SES). At SES sites, delayed endothelial healing effects were noted, whereas no such effects were observed in Pitava-NP-eluting stent sites.. Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as SES without the delayed endothelial healing effects of SES in a porcine coronary artery model. This nanotechnology platform could be developed into a safer and more effective device in the future.

Topics: Animals; Blotting, Western; Cell Proliferation; Cells, Cultured; Constriction, Pathologic; Coronary Artery Disease; Disease Models, Animal; Drug-Eluting Stents; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Microscopy, Electron, Scanning; Nanoparticles; Quinolines; Swine

There has been a steady increase in the epidemiology of obesity over the last 30 years with developed countries leading the way. Oxidative stress was believed to be the principle contributor to the development of cardiovascular disorders that linked with obesity.. To evaluate the enhancement of antioxidant defense mechanism by Pitavastatin (PTV) and Rosuvastatin (RSV) on obesity-induced oxidative stress in Wistar rats.. Fifty Wistar albino rats were divided into five groups. High fat diet (HFD, 20 g/day/rat) pellets were given for 28 days to produce obesity-induced oxidative stress in Wistar rats. Oral administration of HFD along with PTV, RSV and Orlistat [(HFD for 28 days + from 8th day PTV (1 mg/kg), RSV (5 mg/kg) and Orlistat (10 mg/kg) to 28th day] were given respectively.. Both PTV and RSV produced significant (p < 0.01) reduction in serum apolipoprotein-B (Apo-B), total cholesterol (TC), triglycerides (TGs), cardiac-lipid peroxides (TBARS) levels and elevation in serum high density lipoprotein (HDL-C), cardiac antioxidant enzymes [glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catase (CAT)] levels.. Results were comparable with Orlistat, a standard antiobesity drug and present initial evidence that Pitavastatin and Rosuvastatin are useful for the treatment of obesity by enhancing the antioxidant defense mechanism. However, the effects of PTV were more prominent than RSV. The present findings of Pitavastatin and Rosuvastatin raise the possibility of a new application as an antiobesity therapeutic modality.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Antioxidants; Apolipoproteins B; Cholesterol, HDL; Disease Models, Animal; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Lipid Peroxides; Myocardium; Obesity; Orlistat; Oxidative Stress; Pyrimidines; Quinolines; Rats; Rats, Wistar; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome; Triglycerides

To examine and compare the pleiotropic anti-inflammatory effects and the long-term effects of atorvastatin and pitavasatin in mouse model of Alzheimer's disease (AD).. We examined the effects of two strong statins on senile plaque (SP) size and inflammatory responses in the brain of an amyloid precursor protein (APP) transgenic (Tg) mouse. We gave the Tg mice either atorvastatin or pitavastatin from 5-20 months of age, and performed immunohistological analysis [SP area, monocyte chemotactic protein 1 (MCP-1)-positive neurons, ionized calcium-binding adaptor molecule 1 (Iba-1)-1-positive microglia, and tumor necrosis factor α (TNF-α)-positive neurons] every 5 months.. In the APP-Tg mice treated with both statins, the number of MCP-1-positive neurons was reduced at 10 months, that of Iba-1-positive microglia was reduced at 15 months, and that of TNF-α-positive neurons and the mean total SP area decreased at 15-20 months, compared with APP-Tg mice with vehicle treatment.. The protective effect of these statins took 5 months to reach significance in these mice, and the order of sensitivity to statin treatment was MCP-1>Iba-1>TNF-α>SPs. Proinflammatory responses including MCP-1, Iba-1, and TNF-α preceded and possibly contributed to SP formation. Pitavastatin has the same significant pleiotrophic effect to prevent and ameliorate inflammation and also has a long-term effect compared with atorvastatin, and both of them have high potential for a preventative approach in patients at risk of AD.

Topics: Alzheimer Disease; Animals; Atorvastatin; Brain; Disease Models, Animal; Female; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Inflammation; Mice; Mice, Transgenic; Plaque, Amyloid; Pyrroles; Quinolines

Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions, improve behavioral memory and reduce senile plaque (SP). Thus, we examined cognitive function, the serum level of lipids, senile plaque (SP), and the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3mg/kg/day, p.o.) were administered from 5 to 20 months of age. These 2 statins improved behavioral memory and reduced the numbers of SP at 15 and 20 M without affecting serum lipid levels. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near SP. There was also an increase in intensity and numbers of glial fibrillary acidic protein (GFAP) positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Anticholesteremic Agents; Atorvastatin; Cholesterol; Collagen Type IV; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glial Fibrillary Acidic Protein; Glucosamine; Heptanoic Acids; Humans; Matrix Metalloproteinase 9; Maze Learning; Methylcellulose; Mice; Mice, Transgenic; Mutation; Pyrroles; Quinolines

Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated γ-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either γ-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction.

Topics: Animals; Arteries; Blood Circulation; Blotting, Western; Cell Line; Disease Models, Animal; Hindlimb; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Quinolines; Receptor, Notch1; Signal Transduction; Vascular Endothelial Growth Factor A

Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.

Topics: Animals; Antibodies; CD36 Antigens; Cell Line; Cell Proliferation; Diabetes Mellitus, Type 2; Disease Models, Animal; Epidermis; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Keratinocytes; Lipid Peroxidation; Lipoproteins, LDL; Lysophosphatidylcholines; Mice; Mice, Inbred C57BL; Mice, Obese; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Quinolines; Skin; Thiobarbituric Acid Reactive Substances; Vascular Endothelial Growth Factor A

In contrast to cerebral cortical neurons, the extent of damage to cells of the cerebellum in Alzheimer's disease (AD) is still a matter of debate. Here, we examined pathological changes in the cerebellar Purkinje cells (PCs) of AD model mice (amyloid precursor protein transgenic (APP-Tg) mice) at 10, 15, and 20 months (M) of age, and investigated the possible protective effect of two strong statins (atorvastatin at 30 mg/kg/day or pitavastatin at 3mg/kg/day, p.o.) by administering these statins from 5 to 20 M. The number of PCs detected by hematoxylin-eosin staining in APP-Tg mice was approximately 60% of the number in non-Tg mice at 10 M, and this progressively reduced with age until 20 M. Moreover, the number of monocyte chemotactic protein 1 (MCP-1)-positive PCs and tumor necrosis factor alpha (TNF-α)-positive PCs was also reduced in the transgenics. In contrast, the APP-Tg mice treated with either of the two statins showed a significant recovery in the number of PCs, and MCP-1 (at 20 M) and TNF-α (at 15 and 20 M) staining in PCs was preserved. Because MCP-1 and TNF-α play important roles in maintaining the synaptic network in PCs, the present study suggests that atorvastatin and pitavastatin can maintain the number of PCs and their synaptic networks in the AD cerebellum.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Chemokine CCL2; Disease Models, Animal; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Mice; Mice, Transgenic; Purkinje Cells; Pyrroles; Quinolines; Tumor Necrosis Factor-alpha

Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg·kg·d, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, ±LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-α level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IκB kinase/nuclear factor-kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IκB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis.

Topics: Animals; Apoptosis; Blotting, Western; Cardiotonic Agents; Disease Models, Animal; Hemodynamics; I-kappa B Kinase; Male; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Quinolines; Rats; Rats, Wistar; Up-Regulation

Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions. Thus, we examined the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3 mg/kg/day, p.o.) were administered from 5 to 20 months of age. Changes in the NVU, including the endothelium and basement membrane, as well as astrogliosis and matrix metalloproteinase-9 (MMP-9) activation, were assessed. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near senile plaques (SPs). There was also an increase in intensity and number of glial fibrillary acidic protein (GFAP)-positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Treatment with atorvastatin or pitavastatin ameliorated the activation of MMP-9. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Blotting, Western; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Female; Fluorescent Antibody Technique; Heptanoic Acids; Humans; Immunohistochemistry; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neuroprotective Agents; Pyrroles; Quinolines

Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.. We treated 3T3-L1 preadipocytes with 10-100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.. Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (>150 microm in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5+/-3.8 microg/ml vs. 8.3+/-1.5 microg/ml, p<0.05). Moreover, the area under the time-glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p<0.05 vs. untreated controls).. Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Blood Glucose; Cell Size; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Female; Glucose Transporter Type 4; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy; Insulin; Insulin Resistance; Lipogenesis; Lipoprotein Lipase; Mice; Obesity; Plasminogen Activator Inhibitor 1; Quinolines; Time Factors; Triglycerides

We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals.. Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle.. Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects.. The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cells, Cultured; Chronic Disease; Collateral Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Electric Stimulation; Endothelial Cells; Feasibility Studies; Hindlimb Suspension; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Injections, Intramuscular; Ischemia; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Nanoparticles; Neovascularization, Physiologic; Oxygen; Phthalazines; Protein Kinase Inhibitors; Pyridines; Quinolines; Rabbits; Regional Blood Flow; Time Factors; Vascular Endothelial Growth Factor Receptor-1

Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.. In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.. NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Topics: Angiogenesis Inducing Agents; Angiogenic Proteins; Animals; Cells, Cultured; Disease Models, Animal; Drug Carriers; Endothelium, Vascular; Enzyme Inhibitors; Hindlimb; Humans; Injections, Intramuscular; Ischemia; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Nanoparticles; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Proto-Oncogene Proteins c-akt; Quinolines; Regional Blood Flow; Time Factors

Statins are commonly used lipid-lowering drugs that reduce the risk of cardiovascular morbidity and mortality. Although recent studies have pointed to chemopreventive effects of statins against various cancers, their efficacy for gastric cancer is unclear. Here, we examined the effects of pitavastatin, a lipophilic statin, on Helicobacter pylori (H. pylori)-associated stomach carcinogenesis and gastritis using Mongolian gerbil and mouse models. The animals were allocated to H. pylori + N-methyl-N-nitrosourea administration (gerbils, 52 weeks) or H. pylori infection alone groups (gerbils and mice, 12 weeks). After H. pylori infection, they were fed basal diets containing 0 to 10 ppm of pitavastatin. The incidences of H. pylori-associated gastric adenocarcinomas and degrees of chronic gastritis were not decreased by pitavastatin compared with those of control values. Expression of interleukin-1beta and tumor necrosis factor-alpha mRNAs in the pyloric mucosa was markedly up-regulated in pitavastatin-treated animals. Furthermore, in the H. pylori-infected groups, serum total cholesterol, triglyceride, and low-density lipoprotein levels were significantly increased by pitavastatin treatment, contrary to expectation. In the short-term study, H. pylori-infected gerbils and mice also showed significant up-regulation of serum triglyceride levels by pitavastatin, whereas total cholesterol was markedly reduced and low-density lipoprotein exhibited a tendency for decrease in noninfected animals. These findings indicate pitavastatin to be ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in H. pylori-infected gerbils. Our serologic results also suggest that the H. pylori infection and consequent severe chronic gastritis interfere with the cholesterol-lowering effects of pitavastatin.

Topics: Animals; Carcinoma; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Lipids; Male; Mice; Mice, Inbred C57BL; Models, Biological; Quinolines; Rodentia; Stomach Neoplasms; Treatment Failure

Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.

Topics: Acetylcholinesterase; Administration, Oral; Alzheimer Disease; Animals; Brain; Celecoxib; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Escape Reaction; Female; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indans; Injections, Intraventricular; Male; Maze Learning; Mental Recall; Mice; Nootropic Agents; Piperidines; Pyrazoles; Quinolines; Streptozocin; Sulfonamides; Thiobarbituric Acid Reactive Substances

Several animal and human studies suggest pharmacological approaches may prevent steroid-induced osteonecrosis (ON). We asked whether the newly developed 3-hydroxymethyl-3-glutaryl-CoA (HMG-CoA) reductase inhibitor, pitavastatin, could prevent steroid-induced ON in rabbits. We injected 65 adult male Japanese white rabbits once with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were divided into two groups; one group of 35 rabbits received pitavastatins (PS), and the other group of 30 rabbits received no prophylaxis (CTR). Hematological examinations were performed just before the steroid injection (0 weeks) and at 1 and 2 weeks after steroid injection; both the femora and the humeri were histologically examined 2 weeks postinjection. The incidence of histologic changes consistent with early ON in the PS group (13 of 35; 37%) was lower in comparison to the CTR group (21 of 30; 70%). The size of the bone marrow fat cells in the PS group (56.6 +/- 10 microm) was smaller than those in the CTR group (60 +/- 4 microm). The data suggest pitavastatin has the potential to lower the incidence of steroid-induced ON in rabbits.

Topics: Adipocytes; Animals; Bone Marrow Cells; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Femur; Femur Head Necrosis; Humerus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Methylprednisolone; Methylprednisolone Acetate; Osteonecrosis; Pilot Projects; Quinolines; Rabbits; Time Factors

Incomplete recovery of myocardial contraction after reperfusion following brief ischemia is called the "stunning phenomenon" in an animal experiment. A hydrophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) does not affect this phenomenon, but lipophilic statins further reduce the contraction during reperfusion. The effects of novel hydrophilic rosuvastatin and lipophilic pitavastatin on myocardial stunning in dogs were examined. In a preliminary experiment in vitro, pitavastatin reduced L6 cell viability at 10(-6) M and higher, whereas rosuvastatin and pravastatin up to 10(-5) M did not show such effects. An empty capsule or a capsule filled with rosuvastatin (2 mg/kg per day) or pitavastatin (0.4 mg/kg per day) was orally administered to dogs. After 3 weeks, both statins lowered the serum cholesterol level to the same extent. Under pentobarbital anesthesia, dogs were subjected to 15-min ischemia followed by 120-min reperfusion. Ischemia arrested the myocardial contraction in the ischemic area, and reperfusion recovered it but incompletely, showing the stunning phenomenon. Rosuvastatin did not modify the stunning phenomenon, while pitavastatin further deteriorated the myocardial contraction during reperfusion.

Topics: Administration, Oral; Animals; Cell Line; Cell Survival; Cholesterol; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Energy Metabolism; Female; Fluorobenzenes; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Muscle, Skeletal; Myocardial Contraction; Myocardial Ischemia; Myocardial Stunning; Myocardium; Pyrimidines; Quinolines; Rats; Rosuvastatin Calcium; Sulfonamides; Time Factors

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Blood Glucose; Body Weight; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Down-Regulation; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Mesangial Cells; Mice; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Quinolines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1

We investigated the effects of pitavastatin on angiogenesis and perfusion in C3H/He mice with unilateral hind limb ischemia.. C3H/He mice treated with saline (n = 15) or pitavastatin (1 mg.kg(-1).d(-1), n = 15) per gavage for 1 week underwent unilateral hind limb ischemia surgery and were treated for another 5 weeks. Hind-limb blood flow was measured by Laser Doppler perfusion imager (LDPI, ischemic/nonischemic limb, %) at baseline, immediately after ischemia and weekly thereafter for 5 weeks. Endpoints included local vessel counts by immunofluorescence, phospho-Akt positive cell counts by immunoenzyme histochemical technique, vascular endothelial growth factors (VEGFs) expression in ischemic limbs by Western blot and serum nitric oxide metabolite (NOx) by chrome dioxide Griess method.. Lower extremity perfusion was significantly improved in pitavastatin treated mice vs. controls as measured by LDPI% at 1 week post ischemia and thereafter (P < 0.05). Pitavastatin treatment was associated with significantly increased capillary count [(47 +/- 11) vs. (26 +/- 14)/per high-power field (x 200), P < 0.05] and greater percentage of phospho-Akt positive cells [(6 +/- 1) vs. (2 +/- 0)/per high-power field (x 200), P < 0.05] in ischemic limbs. Serum NOx [(77.3 +/- 21.8) vs. (52.1 +/- 11.2) mol/L, P < 0.05) and VEGF protein expression in ischemic limbs were also significantly increased in pitavastatin group than those in control group.. Pitavastatin enhances angiogenesis and perfusion in CsH/He mice with limb ischemia.

Topics: Animals; Disease Models, Animal; Ischemia; Lower Extremity; Male; Mice; Mice, Inbred C3H; Neovascularization, Physiologic; Nitric Oxide; Quinolines; Vascular Endothelial Growth Factors

To evaluate the relation between statin therapy, vascular endothelial growth factor (VEGF) expression, vascular leakage, and CNV size in experimentally induced choroidal neovascularization (CNV).. Wild-type (C57 Bl/6J) mice received pitavastatin 0.18 mg/kg per day (group 1), 1.8 mg/kg per day (group 2) or 18 mg/kg per day (group 3) for 3 days before laser-induced CNV and continued to receive the drug for 14 days. Serum total cholesterol levels were measured by spectrophotometry. Fluorescein angiograms were graded by masked observers. VEGF protein levels from retinal lysates were measured and CNV area was assessed by histology.. Pitavastatin did not reduce total serum cholesterol at any of the doses used. The incidence rate ratios for development of clinically significant CNV leakage was 0.62 (95% CI, 0.46-0.84) for group 1, 0.56 (95% CI, 0.28-1.10) for group 2, and 1.22 (95% CI, 1.01-1.48) for group 3 (P=0.002, 0.09, and 0.04, respectively). Mean CNV area increased by 13%, 22%, and 95% in groups 1, 2, and 3, respectively (P>0.05). Normalized VEGF levels did not mirror the observed changes in fluorescein leakage and CNV area in histologic examination.. Pitavastatin therapy for experimental CNV in wild-type mice resulted in reduced fluorescein leakage at a dose of 0.18 mg/kg per day. The higher dose of 18 mg/kg per day resulted in increased fluorescein leakage and a trend toward an increase in CNV size, indicating a potentiating effect in choroidal neovascular disease.

Topics: Animals; Cholesterol; Choroidal Neovascularization; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fluorescein; Fluorescein Angiography; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred C57BL; Permeability; Quinolines; Retina; Vascular Endothelial Growth Factor A

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.

Topics: Animals; Blood Pressure; Cardiac Output, Low; Disease Models, Animal; Endothelin-1; Extracellular Matrix; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Lipids; Male; Matrix Metalloproteinases; Protein Prenylation; Quinolines; Rats; Rats, Inbred Dahl; Receptors, Endothelin; Renin-Angiotensin System; Survival Rate; Tissue Inhibitor of Metalloproteinases; Ventricular Remodeling

This study aimed to clarify the effect of statins on spontaneous stroke and to examine the antioxidative effect in artificial transient middle cerebral artery occlusion (tMCAO).. Stroke-prone spontaneous hypertensive rats (SHR-SP) were treated with pitavastatin, atorvastatin, simvastatin, or vehicle for 4 weeks. Physiological parameters, serum lipids, and infarct volumes were examined. The markers for oxidative stresses on lipids and DNA were immunohistochemically detected in vehicle-treated or simvastatin-treated SHR-SP with tMCAO.. Atorvastatin and simvastatin decreased infarct volumes, with simvastatin most effective. Simvastatin significantly reduced immunoreactivities for oxidative stress markers for lipids and DNA in neurons after tMCAO.. The results suggest that the antioxidative properties of statins may be implicated in their beneficial effects against neuronal damage in cerebral ischemia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Atorvastatin; Blood Pressure; Body Weight; Deoxyguanosine; Disease Models, Animal; Heptanoic Acids; Hydroxymethylglutaryl CoA Reductases; Infarction, Middle Cerebral Artery; Lipids; Lysine; Oxidative Stress; Pyrroles; Quinolines; Rats; Rats, Inbred SHR; Simvastatin; Survival Analysis

We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.

Topics: Animals; Cell Count; Disease Models, Animal; Enzyme Inhibitors; Gerbillinae; Hippocampus; Immunohistochemistry; Interneurons; Ischemic Attack, Transient; Male; Nitric Oxide Synthase Type I; Parvalbumins; Quinolines; Time Factors

Increased cardiovascular mortality is an unresolved problem of chronic renal failure. Cardiac hypertrophy, observed in many patients with chronic renal failure, is a major risk factor for cardiovascular death. The purpose of the present study was to examine the effects of pitavastatin on cardiac hypertrophy in a progressive renal injury rat model by subtotal nephrectomy (SNx). Because we previously reported that angiotensin II played a pivotal role in cardiac hypertrophy of SNx rats, we first investigated the effects of pitavastatin on angiotensin II-induced activation of extracellular signal-regulated kinase (ERK) and serum response element (SRE) DNA-binding activity using neonatal rat cardiomyocytes. Angiotensin II-induced ERK activation was attenuated by pretreatment with pitavastatin. Luciferase assay revealed that angiotensin II-induced increase in SRE DNA-binding activity was inhibited by pitavastatin. We next examined the effect of pitavastatin on cardiac hypertrophy of SNx rats in vivo. Treatment with pitavastatin prevented ERK activation and cardiac hypertrophy in SNx rats without changes in blood pressure. The increased expression of atrial natriuretic factor mRNA in SNx rat hearts was significantly attenuated by the treatment with pitavastatin. These results suggest that pitavastatin has a beneficial effect on cardiac hypertrophy in renal failure through preventing the activation of ERK.

Topics: Angiotensin II; Animals; Animals, Newborn; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Disease Progression; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Kidney; Male; Myocytes, Cardiac; Nephrectomy; Phosphorylation; Quinolines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoconstrictor Agents

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol; Dietary Fats; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Quinolines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Neointimal hyperplasia plays a crucial role in restenosis after stenting. The severity of neointimal thickness correlates with inflammatory reactions in the injured vessel and statins can inhibit inflammation. Pitavastatin has favorable effects on plasma lipoproteins and inflammation. Thus, we hypothesized that pitavastatin might inhibit the early inflammatory response, resulting in prevention of neointimal hyperplasia in porcine coronary arteries after stenting. Pitavastatin (18 coronaries, 40 mg per day) or placebo (20 coronaries) was administered orally from 7 days before stenting until the time of euthanasia at 3 or 28 days after stenting. The coronary artery of the animals was injured with an oversized metallic coil stent. Inflammatory cell infiltration was evaluated by scanning electron microscopy and was significantly reduced in the treated vessels compared to controls. On Day 28, intravascular ultrasound analysis revealed the neointimal area was significantly less at the stent site in the pitavastatin group than in the placebo. Histopathologic assessment showed significantly decreased in neointimal area in the pitavastatin group compared to the placebo (2.16 +/- 0.13 mm(2) versus 2.88 +/- 0.25 mm(2), p = 0.029), whereas the mean injury score in the pitavastatin group was larger than in the placebo group. In conclusion, Pitavastatin inhibited neointimal hyperplasia after stenting through a reduction of inflammatory reactions.

Topics: Animals; Coronary Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Female; Hypertrophy; Male; Microscopy, Electron, Scanning; Probability; Quinolines; Random Allocation; Reference Values; Sensitivity and Specificity; Stents; Swine; Tunica Intima; Ultrasonography, Interventional

Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is a potent cholesterol-lowering drug that reduces the risk of myocardial infarction and stoke. In this study, we examined its neuroprotective effects against hippocampal CA1 neuronal damage following transient cerebral ischemia in gerbils. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 5 min. Pitavastatin, at a dose of 3, 10 or 30 mg/kg, was administered orally twice a day for 5 consecutive days and transient cerebral ischemia was induced in mice 1 h after the last treatment with pitavastatin. Histopathological observations showed that neuronal damage to the hippocampal CA1 neurons, which was observed 5 days after ischemia in animals, was prevented by pitavastatin treatment. Immunohistochemical staining for copper/zinc superoxide dismutase (SOD) and manganese SOD decreased in the hippocampal CA1 sector of gerbils 2 days after ischemia when histological neuronal destruction was not yet found, but was clearly observed in pitavastatin-treated animals. These results indicate that pitavastatin can protect dose-dependently against ischemia-induced neuronal damage and that the mechanism of the neuroprotection may be related to the preservation of SODs, especially copper/zinc-SOD. This in part explains how pitavastatin therapy, which targets free radicals, has beneficial effects against disorders including ischemic stroke.

Topics: Animals; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Free Radicals; Gerbillinae; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Ischemic Attack, Transient; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Quinolines; Superoxide Dismutase

The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model.. We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits.. Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK.. Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).

Topics: Administration, Oral; Animals; Arteriosclerosis; Biological Availability; Cholesterol, HDL; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Nitric Oxide; Quinolines; Rabbits; Triglycerides; Up-Regulation

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Bone Marrow Cells; Disease Models, Animal; Enzyme Inhibitors; Hematopoietic Stem Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Muscle, Smooth; Quinolines

The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3, 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride. 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect.

Topics: Animals; Apolipoproteins B; Cholesterol; Chromatography, High Pressure Liquid; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Guinea Pigs; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, VLDL; Liver; Male; Quinolines; Receptors, LDL; Simvastatin; Sterols; Triglycerides