pitavastatin and Hypertrophy

Clinical studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, can potentially inhibit chronic heart failure. In the Stat-LVDF study, a difference was noted in terms of the effect of lipophilic pitavastatin (PTV) and hydrophilic rosuvastatin (RSV) on plasma BNP, suggesting that statin lipophilicity and pharmacokinetics change the pleiotropic effect on heart failure in humans. Therefore, we assessed the beneficial effects of PTV on hypertrophy in cardiac myocytes compared with RSV at clinically used doses. Cultured cardiomyocytes were stimulated with 30 μM phenylephrine (PE) in the presence of PTV (250 nM) or RSV (50 nM). These doses were calculated based on the maximum blood concentration of statins used in clinical situations in Japan. The results showed that PTV, but not RSV, significantly inhibits the PE-induced increase in cell size and leucine incorporation without causing cell toxicity. In addition, PTV significantly suppressed PE-induced mRNA expression of hypertrophic response genes. PE-induced ERK phosphorylation was inhibited by PTV, but not by RSV. Furthermore, PTV significantly suppressed the angiotensin-II-induced proline incorporation in primary cultured cardiac fibroblasts. In conclusion, a clinical dose of PTV was noted to directly inhibit cardiomyocyte hypertrophy and cardiac fibrosis, suggesting that lipophilic PTV can be a potential drug candidate against chronic heart failure.

Topics: Actins; Animals; Atrial Natriuretic Factor; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy; Leucine; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phosphorylation; Quinolines; Rats, Sprague-Dawley; RNA, Messenger; Rosuvastatin Calcium

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

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