Lipophilic statins augment inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes

Nitric oxide production by inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of cardiovascular dysfunc tion. We in vestigated the effects of statins on iNOS expression and subsequent nitric oxide synthesis in cardiac myocytes and the mechanism by which statins exer t their effects. We measured the production of nitrite, a stable metabolite of nitric oxide, in cultured neonatal rat cardiac myocytes with the Griess reagent. iNOS mRNA and protein expression were assayed by reverse transcri ption polymerase chain reaction and Western blotting, respectively. The lip ophilic statins fluvastatin and lovastatin significantly increased interleu kin-1 beta -induced nitrite production by cardiac myocytes, whereas hydroph ilic pravastatin did not. Increased nitrite production by fluvastatin was a ccompanied by increased iNOS mRNA and protein accumulation. Exogenous meval onate, but not squalene, significantly blocked the stimulatory effect of fl uvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosph ate also reversed the effect of fluvastatin. Furthermore, both Rho inhibito r C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased int erleukin-1 beta -induced nitrite accumulation in cardiac myocytes. These re sults demonstrated that lipophilic statins upregulate iNOS expression and s ubsequent nitric oxide formation in cardiac myocytes via inhibition of Rho.