Pitavastatin at low dose activates endothelial nitric oxide synthase through PI3K-AKT pathway in endothelial cells.
Pitavastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that is used for suppressing cholesterol biosynthesis. Previously, we have reported that pitavastatin induces the activation of endothelial nitric oxide synthase (eNOS) and increases nitric oxide (NO) production in vascular endothelial cells (EC). However, the mechanism of eNOS activation by pitavastatin remains unknown. Here, we examined the implications of pitavastatin-induced signaling in eNOS phosphorylation in EC. We found that treatment of EC with a low dose of pitavastatin induced eNOS phosphorylation at Ser-1177, activated Akt phosphorylation at Ser-473 in a time-and dose-dependent manner, and increased NO production. These processes were suppressed by the addition of either mevalonic acid (MEV) or geranylgeranyl pyrophosphate (GGPP). In addition, northern blot analysis revealed that pitavastatin did not increase eNOS mRNA expression level in EC. These results suggest that the activation of eNOS with a low dose of pitavastatin (0.1 microM) involves phosphoinositide 3-kinase and the Akt pathway and produces NO in EC, which is dependent on post-transcriptional regulation. This pathway is critical for cellular responses that contribute to EC function.
Wang
Juyong
J
Department of Clinical Laboratory Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 21st Century COE Program, 2630 Sugitani, Toyama 930-0194, Japan.
Tokoro
Takashi
T
Matsui
Koshi
K
Higa
Susumu
S
Kitajima
Isao
I
D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007202:Indicators and Reagents; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical
D017077:Culture Media, Conditioned; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D012694:Serine; C496314:NOS3 protein, human; C494918:AKT1 protein, human; C108475:pitavastatin