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Down-Regulation of Na⁺/Ca²⁺ Exchanger by Fluvastatin in Rat Cardiomyoblast H9c2 Cells: Involvement of RhoB in Na⁺/Ca²⁺ Exchanger mRNA Stability

Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima Japan (S.M., I.M., J.K.), Department of Pharmacology, Fukuoka University School of Medicine, Fukuoka, Japan (T.I.); and Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, Kyushu University, Fukuoka, Japan (H.K.)

We investigated the effect of fluvastatin (Flv), an HMG-CoA reductase inhibitor, on Na⁺/Ca²⁺ exchanger 1 (NCX1) expression in H9c2 cardiomyoblasts. Reverse transcriptase-polymerase chain reaction analyses revealed that Flv decreased NCX1 mRNA in a concentration- and time-dependent manner and NCX1 protein. This effect of Flv was caused by the inhibition of HMG-CoA reductase, because Flv did not affect the NCX1 mRNA in the presence of mevalonate. Flv-induced down-regulation of NCX1 mRNA was also cancelled by farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), suggesting an involvement of small G-proteins. However, overexpression of neither constitutive active RhoA nor Ras affected NCX1 mRNA. In contrast, intracellular expression of C3 toxin, a specific inhibitor of Rho family proteins, decreased NCX1 mRNA, suggesting that Flv decreases NCX1 mRNA by inhibiting a signaling pathway of Rho family proteins other than RhoA. On the other hand, lysophosphatidylcholine (LPC), an activator of Rho signaling, increased both NCX1 mRNA and protein in a C3 toxin-sensitive manner. Western blot analyses revealed that membrane-associated RhoB, which is isoprenylated by either FPP or GGPP, was decreased by Flv but was increased by LPC. Selective inhibition of gene expression by short interfering RNA duplex showed that RhoB but not RhoA is involved in the regulation of NCX1 mRNA and protein. When transcription was blocked by 5,6-dichlorobenzimidazole riboside, the NCX1 mRNA stability was decreased by Flv. Long-term treatment of rat with Flv in vivo also down-regulated the cardiac NCX1 mRNA. These results suggest that a RhoB-mediated signaling pathway regulates cardiac NCX1 levels by controlling the NCX1 mRNA stability.

Address correspondence to: Dr. Junko Kimura, Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan. E-mail: jkimura{at}fmu.ac.jp

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