pitavastatin and Fibrosis

The aim of the present study was to assess the effect of early statin therapy on fibrous-cap thickness in coronary plaques of patients with acute coronary syndrome (ACS) by using optical coherence tomography.. Statins can contribute to the stabilization of coronary plaques.. This is a prospective, randomized, active-controlled, single-center study. Patients with ACS and untreated dyslipidemia were enrolled and randomly allocated (ratio 1:1) to either the early statin group (received pitavastatin 4 mg/day from baseline) or the late statin group (received pitavastatin 4 mg/day from 3 weeks after the baseline). Optical coherence tomography was performed at baseline, 3-week, and 36-week follow-up to assess nonculprit coronary plaques in 53 patients.. Between baseline and 3-week follow-up, fibrous-cap thickness increased in the early statin group (140 μm [interquartile range (IQR):120 to 170 μm] to 160 μm [IQR: 130 to 190 μm]; p = 0.017), but decreased in the late statin group (135 μm [IQR: 110 to 183 μm] to 130 μm [IQR: 108 to 160 μm]; p = 0.020). The percentage of increase in fibrous-cap thickness between baseline and 3-week follow-up was significantly greater in the early statin group compared with the late statin group (8.3% [IQR: 0.0% to 21.4%] vs. -5.8% [IQR: -16.0% to 0.0%]; p < 0.001). Between baseline and 36-week follow-up, fibrous-cap thickness increased comparably in the 2 groups.. Early therapy with pitavastatin 4 mg/day for patients with ACS provided an increase in fibrous-cap thickness in coronary plaques during the first 3 weeks of follow-up and a further increase during 36 weeks of follow-up. The study was registered with UMIN Clinical Trial Registry (Effect of PitavaStatin on Coronary Fibrous-cap Thickness-Assessment by Fourier-Domain Optical CoheRence Tomography [ESCORT]; UMIN000002678).

Topics: Acute Coronary Syndrome; Aged; Coronary Vessels; Female; Fibrosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Quinolines; Time Factors; Tomography, Optical Coherence; Treatment Outcome

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

Renal dysfunction is an independent risk factor for cardiovascular events. However, little is known regarding the impacts of renal dysfunction on coronary atherosclerosis.. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the TRUTH study using virtual histology intravascular ultrasound in 164 patients with angina pectoris. We analyzed correlations between the estimated glomerular filtration rate (eGFR) and coronary atherosclerosis before and during statin therapy.. Baseline eGFR was 64.5 mL/min per 1.73 m(2) . Serum low-density lipoprotein cholesterol level decreased significantly from 132 to 85 mg/dL (-35%, P < 0.0001) after 8 months. Weak, but significant, negative correlations were observed between eGFR and external elastic membrane volume (r = -0.228, P = 0.01) and atheroma volume (r = -0.232, P = 0.01) at baseline. The eGFR was also negatively correlated with fibro-fatty volume (r = -0.254, P = 0.005) and fibrous volume (r = -0.241, P = 0.008) at baseline. Multivariate regression analyses showed that eGFR was a significant independent predictor associated with statin pre-treatment volume in fibro-fatty (β = -0.23, P = 0.01) and fibrous (β = -0.203, P = 0.02) components. Furthermore, eGFR was positively correlated with volume change in the fibro-fatty component during statin therapy (r = 0.215, P = 0.02).. Decreased eGFR is associated with expanding remodelling and a greater atheroma volume, particularly the fibro-fatty and fibrous volume before statin therapy in patients with normal to mild renal dysfunction. Reduction of fibro-fatty volume during statin therapy gradually accelerated with decreasing renal function.

Topics: Aged; Biomarkers; Coronary Artery Disease; Coronary Vessels; Dyslipidemias; Female; Fibrosis; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Kidney; Kidney Diseases; Lipids; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Pravastatin; Prospective Studies; Quinolines; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography, Interventional

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are widely used to lower plasma cholesterol levels, have been reported to have various pleiotropic effects such as protective effect of endothelial cells, angiogenic effect, antioxidant effect and anti-inflammatory effect. It is unclear, however, whether statins have any effects on the progression from left ventricular (LV) hypertrophy to heart failure in the established hypertrophied heart.. C57BL/6 mice were treated with pitavastatin (pitava) or vehicle (control) from 2 weeks (established hypertrophy stage) after transverse aortic constriction (TAC) and the treatment was continued for 4 weeks. Pitavastatin significantly inhibited the progression from LV hypertrophy to heart failure as assessed on echocardiography. The cardiomyocyte cross-sectional area was significantly increased in the control group compared to the sham-operated mice (sham group), but it was not significantly different between the control group and the pitava group at 6 weeks after TAC. Moreover, pitavastatin induced myocardial angiogenesis (ratio of number of endothelial cells to cardiomyocytes) and decreased the myocardial fibrosis and oxidative stress. The expression of angiopoietin-1 in the heart was significantly increased by pitavastatin at 6 weeks after TAC.. Pitavastatin has preventive effects on the progression of heart failure even in the hypertrophied heart.

Topics: Angiopoietin-1; Animals; Blood Pressure; Fibrosis; Gene Expression Regulation; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Mice; Myocardium; Neovascularization, Pathologic; Oxidative Stress; Quinolines; Time Factors

Sphingosine kinase 1 (SPHK1), its product sphingosine-1-phosphate (S1P), and S1P receptor subtypes have been suggested to play protective roles for cardiomyocytes in animal models of ischaemic preconditioning and cardiac ischaemia/reperfusion injury. To get more insight into roles for SPHK1 in vivo, we have generated SPHK1-transgenic (TG) mice and analysed the cardiac phenotype.. SPHK1-TG mice overexpressed SPHK1 in diverse tissues, with a nearly 20-fold increase in enzymatic activity. The TG mice grew normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Unexpectedly, TG mice with high but not low expression levels of SPHK1 developed progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile TG mice with pitavastatin, an established inhibitor of the Rho family G proteins, or deletion of S1P3, a major myocardial S1P receptor subtype that couples to Rho GTPases and transactivates Smad signalling, both inhibited cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, which reduces reactive oxygen species (ROS), also inhibited cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct was 30% decreased in SPHK1-TG mice compared with wild-type mice.. These results suggest that chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through ROS mediated by S1P3 and favourable cardioprotective effects.

Topics: Animals; Fibrosis; Fluorescent Antibody Technique; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Neuropeptides; Phosphotransferases (Alcohol Group Acceptor); Quinolines; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; Reactive Oxygen Species; Receptors, Lysosphingolipid; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Sphingosine-1-Phosphate Receptors

Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation and thrombosis, especially in a condition with decreased NO bioavailability. Recently, it has been reported that statins reduce the incidence of atrial fibrillation through attenuation of atrial remodeling; however, the mechanisms have not been completely elucidated. Therefore, we aimed to clarify the beneficial effect of statin on atrial remodeling in condition with reduced NO bioavailability. Endothelial NO synthase(-/-) mice were sham operated or infused with angiotensin II (Ang II) via an osmotic minipump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: pitavastatin, Tempol (a free radical scavenger), or vehicle. Echocardiography and electrocardiography showed that Ang II infusion caused left atrial enlargement and a high incidence of atrial fibrillation, whereas pitavastatin and Tempol prevented these abnormalities. In histological analysis, Ang II-induced atrial interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy were all attenuated by pitavastatin and Tempol. Immunohistochemical staining showed that Ang II downregulated thrombomodulin and tissue factor pathway inhibitor and upregulated tissue factor and plasminogen activator inhibitor 1 in the left atrium and that pitavastatin and Tempol corrected the thrombogenic condition. Moreover, pitavastatin and Tempol reduced Ang II-induced atrial superoxide production and atrial transforming growth factor-beta1 expression and Smad 2/3 phosphorylation. Atrial rac1-GTPase activity, known to activate NADPH oxidase, was attenuated by pitavastatin but not by Tempol. In conclusion, pitavastatin exerts endothelial NO synthase-independent protective actions against Ang II-induced atrial remodeling and atrial fibrillation with enhanced thrombogenicity through suppression of oxidant injury.

Topics: Analysis of Variance; Angiotensin II; Animals; Antioxidants; Atrial Fibrillation; Blood Pressure; Blotting, Western; Cardiomegaly; Cyclic N-Oxides; Echocardiography; Fibrosis; Heart Atria; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Knockout; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Oxidative Stress; Quinolines; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad2 Protein; Smad3 Protein; Spin Labels; Transforming Growth Factor beta1

1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) manifest pleiotropic effects that may contribute to their therapeutic efficacy. However, the mechanism of the beneficial action of statins on cardiac hypertrophy and fibrosis remains unclear. We have now investigated this action of pitavastatin in Dahl salt-sensitive (DS) rats. 2. The DS rats progressively develop marked hypertension when fed a diet containing 8% NaCl from 7 weeks of age. These animals exhibited pronounced cardiac hypertrophy and fibrosis, as well as upregulation of fetal-type cardiac gene expression at 12 weeks of age, compared with DS rats fed a diet containing 0.3% NaCl. The abundance of mRNAs for collagen types I and III, angiotensin-converting enzyme, transforming growth factor-beta1 and connective tissue growth factor was also increased in the heart of rats on the high-salt diet. 3. Treatment of rats on the high-salt diet with a non-antihypertensive dose of pitavastatin (0.3 or 1 mg/kg per day) from 7 to 12 weeks of age attenuated the development of cardiac hypertrophy and fibrosis, as well as inhibiting the upregulation of cardiac gene expression. Pitavastatin also blocked the translocation of RhoA to the membrane fraction of the left ventricle and RhoA activation, as well as the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)-1 and ERK-2 and an increase in the DNA binding activity of serum response factor (SRF) in the heart induced by the high-salt diet. 4. These findings suggest that the effects of pitavastatin on load-induced cardiac hypertrophy and fibrosis are independent of its cholesterol-lowering action and may be mediated, at least in part, through inhibition of RhoA-ERK-SRF signalling.

Topics: Aging; Animals; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Electrophoretic Mobility Shift Assay; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Immunoblotting; Lipids; Male; Myocardium; Quinolines; Rats; Rats, Inbred Dahl; rhoA GTP-Binding Protein; Signal Transduction; Sodium Chloride

We have reported that intermediate conductance Ca(2+)-activated K(+) channels (ImK) showed augmented expression in angiotensin II (AII) type 1 receptor-dependent manner in post-ischemic rat heart. ImK has tyrosine phosphorylation sequence in the C-terminus and motifs for NFkappaB and AP1 in the promoter. While statin inhibits AII-mediated vascular remodeling via anti-inflammatory effect independent of cholesterol lowering. To test the possible effect of statin on expression of ImK, Wistar-Kyoto rats received L-nitro-arginine methyl ester (LNAME: 1 mg/ml in drinking water) for 4 weeks in group L. While in L+P group, rats received both LNAME and pitavastatin (PTV: 1 mg/kg/day in drinking water). Temporal profile of ImK mRNA was examined by RT-PCR using specific primers for ImK.. Long-term LNAME administration produced significant hypertension and resulted in marked microvascular remodeling characterized by medial thickening and perivascular fibrosis of coronary arterioles (100-200 microm in diameter). RT-PCR revealed significant up-regulation of ImK mRNA with two distinct peaks in L group in the early phase (days 3-7) and the late phase (4 weeks). PTV partially inhibited a rise in systolic blood pressure, but completely abolished the first peak of ImK upregulation (0.76 +/- 0.04 vs. 3.96 +/- 1.43 folds at day 7, p < 0.001). Co-treatments with PTV also significantly inhibited medial thickening and perivascular fibrosis. These findings indicate that statin inhibits microvascular remodeling induced by chronic inhibition of NO synthesis through the action independent of cholesterol lowering.

Topics: Animals; Arterioles; Blood Pressure; Coronary Vessels; Fibrosis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Situ Hybridization; Lipids; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Potassium Channels, Calcium-Activated; Quinolines; Rats; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation