atrial-natriuretic-factor and cerivastatin

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