Effects of fluvastatin on Na+/Ca2+ exchanger mRNA levels in H9c2 cells

The Na+/Ca2+ exchanger (NCX) plays a major role in the regulation of intracellular Ca2+ homeostasis in cardiomyocytes. NCX activity and its mRNA levels change in cardiovascular diseases. However, the regulation mechanisms of NCX gene expression are unknown. Here, we investigated the effect of fluvastatin, a HMG-CoA reductase (HMGR) inhibitor, on NCX mRNA levels in H9c2 cells derived from embryonic rat heart. NCX mRNA levels were evaluated by quantitative RT-PCR. Incubation of the cells with 5 μM fluvastatin for 24 hours decreased NCX mRNA levels to 57% of the control. The effect of fluvastatin was concentration- and time-dependent. Fluvastatin at a concentration lower than 0. 2 μM did not affect NCX mRNA levels. The effect of fluvastatin was due to inhibition of HMGR, because an addition of mevalonate in the medium prevented fluvastatin from decreasing NCX mRNA levels. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are downstream metabolites of mevalonate and are essential for isoprenylation of small G proteins. HMGR inhibitors are known to prevent isoprenylation of small G proteins, thereby inhibiting the small G protein-mediated signaling pathway. Addition of either FPP or GGPP prevented fluvastatin-induced decrease in NCX mRNA levels. Our results suggest that NCX gene expression is regulated by small G proteins.