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First published on May 6, 2005; DOI: 10.1124/mol.104.000786

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Received for publication March 31, 2004.
Revised May 5, 2005.
Accepted for publication May 6, 2005.

Down-regulation of Na+/Ca2+ exchanger by fluvastatin in rat cardiomyoblast H9c2 cells; involvement of RhoB in Na+/Ca2+ Exchanger mRNA stability

Sachiko Maeda 1, Isao Matsuoka 2, Takahiro Iwamoto 3, Hitoshi Kurose 4, Junko Kimura 2*

1 Fukushima Medical Univerisity 2 Fukushima Medical University 3 Fukuoka Universiity 4 Department of Pharmacology and Toxicology, Graduate school of Pharmaceutical Science, Kyushu Univers

* Address correspondence to: E-mail: jkimura{at}fmu.ac.jp

Abstract

We investigated the effect of fluvastatin (Flv), a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, on Na+/Ca2+ exchanger 1 (NCX1) expression in H9c2 cardiomyoblasts. RT-PCR analyses revealed that Flv decreased NCX1 mRNA in a concentration- and time-dependent manner and NCX1 protein. This effect of Flv was due to inhibition of HMG-CoA reductase, because Flv failed to 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, neither overexpression of 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. Conversely, lisophosphatidylcholine (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 either by FPP or GGPP, was decreased by Flv, but 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. Chronic 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.


Key words: G protein regulation, Cdc42, rho, rac, other small G proteins, Ion transporters (SERCA, Na/K ATPase, CFTR), Regulation of gene expression, RNA/siRNA


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K. Sakamoto, T. Honda, S. Yokoya, S. Waguri, and J. Kimura
Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers
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