endothelin-1 and cerivastatin

It has been reported that 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors (statins) produce a variety of cardiovascular protective effects independent of their ability to lower total and low-density lipoprotein cholesterol. Recent studies have also reported that statins produce pleiotropic effects through improved endothelial function, enhanced fibrinolysis, and antithrombotic actions. In the present study, we examined the effects of pitavastatin, pravastatin, atorvastatin, and cerivastatin on endothelin (ET)-1 production in cultured porcine aortic endothelial cells (PAECs). Treatment with cerivastatin but not pitavastatin, pravastatin, or atorvastatin decreased basal and TNF-alpha-stimulated ET-1 release from PAECs in a dose-dependent manner (1-10 microM). Northern blot analysis showed that cerivastatin markedly suppressed prepro ET-1 mRNA expression in both conditions. In addition, these inhibitory effects of cerivastatin on ET-1 release and prepro ET-1 mRNA expression were completely abolished by simultaneous treatment with 200 microM mevalonate. Furthermore, cerivastatin did not have any effects on endothelial nitric oxide synthase (eNOS) protein levels, but induced eNOS phosphorylation at Ser1177. From these findings, it is most likely that cerivastatin suppresses ET-1 production, possibly through an increase in eNOS activity and the subsequent nitric oxide production in PAECs. These findings also suggest that cerivastatin may have beneficial effects on ET-1-related diseases.

Topics: Animals; Aorta; Atorvastatin; Cells, Cultured; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nitric Oxide Synthase Type III; Phosphorylation; Pravastatin; Pyridines; Pyrroles; Quinolines; RNA, Messenger; Swine

We investigated the direct effects of cerivastatin on hypertrophy of cultured rat neonatal myocytes induced by endothelin and the mechanism by which cerivastatin exerts its effects. Endothelin significantly increased [14C]phenylalanine ([14C]Phe) incorporation, atrial natriuretic peptide (ANP) release, ANP mRNA expression and cell size. Cerivastatin significantly reduced the increase in [14C]phenylalanine incorporation, ANP peptide release, ANP mRNA expression and cell size induced by endothelin, but pravastatin did not. Exogenous mevalonate completely prevented the inhibitory effect of cerivastatin on [14C]phenylalanine incorporation, ANP release and cell size. Cotreatment with geranylgeranyl pyrophosphate also attenuated the effect of cerivastatin on [14C]phenylalanine incorporation, but cotreatment with farnesyl pyrophosphate or squalene did not. Furthermore, both Rho inhibitor C3 exoenzyme and Rho-dependent kinase inhibitor, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide.2HCl (Y27632) significantly decreased [14C]phenylalanine incorporation, ANP secretion, ANP mRNA expression and cell size. Cerivastatin decreased endothelin-induced Rho protein expression, and mevalonate and geranylgeranyl pyrophosphate reversed this effect. These results suggest that cerivastatin directly attenuates cardiac hypertrophy induced by endothelin in cultured rat myocytes partly by inhibition of the Rho pathway.

Topics: ADP Ribose Transferases; Amides; Animals; Atrial Natriuretic Factor; Botulinum Toxins; Cell Size; Cells, Cultured; Endothelin-1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracellular Signaling Peptides and Proteins; Mevalonic Acid; Myocytes, Cardiac; Phenylalanine; Polyisoprenyl Phosphates; Pravastatin; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Wistar; rho GTP-Binding Proteins; rho-Associated Kinases; RNA, Messenger