Fumie Yokotsuka

Cardioprotective Effects of Pitavastatin on Cardiac Performance and Remodeling in Failing Rat Hearts

BACKGROUND Activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling by statins increases the activity of endothelial nitric oxide synthase (eNOS). We investigate whether statins (pitavastatin) improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, Rho-kinase (ROCK) pathway, and the development of oxidative stress in Dahl salt-sensitive (DS) hypertensive rats with heart failure (DSHF). METHODS Pitavastatin (3 mg/kg per day), or pitavastatin plus specific PI3K inhibitor, wortmannin (1 mg/kg per day), or wortmannin alone were administered from the age of 11-18 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group. RESULTS Decreased end-systolic elastance (Ees) and percent fractional shortening (%FS) in failing rats was significantly ameliorated by pitavastatin, but not pitavastatin plus wortmannin or wortmannin alone. Upregulation of eNOS and Akt phosphorylation by pitavastatin was suppressed by pitavastatin plus wortmannin or wortmannin alone. Pitavastatin effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not pitavastatin plus wortmannin or wortmannin alone. Activated RhoA and myosin light chain phosphorylation and RhoA, ROCK expression was inhibited by pitavastatin or a specific ROCK inhibitor, Y-27632, and downregulated eNOS expression and Akt phosphorylation was ameliorated by Y-27632. Increased expression of NAD(P)H oxidase subunits and activated p65 nuclear factor (NF)-kappaB, p44/p42 extracellular signal-regulated kinases and its downstream effector p90 ribosomal S6 kinase phosphorylation in failing rat hearts was inhibited by pitavastatin. CONCLUSIONS These findings suggest that pitavastatin may improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, the ROCK pathway and oxidative stress.

Effect of Eplerenone on Endothelial Progenitor Cells and Oxidative Stress in Ischemic Hindlimb

BACKGROUND We have demonstrated that angiotensin II receptor blocker (ARB) improved endothelial progenitor cells (EPCs) dysfunction through the antioxidative mechanism. Therefore, we investigate whether the selective mineralocorticoid receptor (MR) antagonist eplerenone improves EPCs function in rat hindlimb ischemia. METHODS Unilateral hindlimb ischemia was surgically induced in Wistar rats. After induced ischemia, rats received eplerenone (30 mg/kg/day), valsartan (3 mg/kg/day), or vehicle for 3 weeks. Peripheral blood mononuclear cells were isolated, subjected to flow cytometric analysis to determine the number of circulating EPCs, cultured to assay EPC colony formation, and subjected to a migration chamber assay to evaluate EPCs migration. RESULTS Blood perfusion by laser Doppler image was significantly higher in eplerenone than in vehicle. Capillary density by isolectin B4 stained of ischemic muscle was significantly increased in eplerenone compared with vehicle. Eplerenone significantly increased the number, colony formation, and migration of EPCs. Levels of endothelial nitric oxide synthase (eNOS) and angiogenic factor such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) protein expression by western blot were significantly higher in eplerenone than in vehicle. Eplerenone significantly decreased the NAD(P)H oxidase p22(phox), p47(phox), gp91(phox) and MR expression and expression of aldosterone effector kinase serum and glucocorticoid-induced protein kinase 1 (Sgk1). These effects of eplerenone are similar extent as valsartan. CONCLUSIONS This study showed that eplerenone improves the proliferation and function of EPCs in rat hindlimb ischemia, suggesting that eplerenone may provide a novel and effective therapeutic strategy for the repair of cardiovascular diseases.

Evaluation of Microvessels in Colorectal Tumors by Narrow Band Imaging Magnification: Including Comparison with Magnifying Chromoendoscopy

AbstractsBackground/AimsNarrow band imaging (NBI) magnification analysis has entered use in clinical settings to diagnose colorectal tumors. Pit pattern analysis with magnifying endoscopy is already widely used to assess colorectal lesions and invasion depth. Our study compared diagnoses by vascular pattern analysis and pit pattern analysis with NBI magnification.MethodsWe examined 296 colorectal lesions—15 hyperplastic polyps (HP), 213 low-grade adenomas (L-Ad), 26 high-grade adenomas (H-Ad), 31 with intramucosal to scanty submucosal invasion (M-Sm-s), and 11 with massive submucosal invasion (Sm-m)—applying the system of Kudo et al. to analyze pit patterns, and the system of Tanaka et al. to analyze and classify vascular patterns by NBI into three categories: type A (hyperplasia pattern), type B (adenomatous pattern), and type C (carcinomatous pattern). Type C cases were subdivided into subtypes C1, C2, and C3. We used this system to examine histology type and invasion depth.ResultsDiagnostic sensitivity, specificity, and accuracy were 100% for both type II pit pattern HP and type A HP. Diagnostic sensitivity, specificity, and accuracy were 85.4, 94.5, and 93.2% for Vi and Vn pit pattern cancer and 95.2, 91.7, and 92.2% for type C cancer (no significant differences in sensitivity, specificity, or accuracy). Diagnostic sensitivity, specificity, and accuracy were comparable for Vi high-grade irregularity and Vn pit pattern Sm-m (90.9, 96.8, and 96.7%) and type C2/C3 Sm-m (90.1, 98.2, and 98.0%), with no significant differences in sensitivity, specificity, or accuracy.ConclusionsVascular pattern analysis by NBI magnification proved comparable to pit pattern analysis.