pitavastatin and Cardiomegaly

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

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

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