| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
(1) Using H9c2 cells derived from rat neonatal cardiac myocytes, we investigated the effect of fluvastatin (Fly) on the expression levels of cardiac type of Na^+/Ca^<2+> exchanger (NCX1). Fluvastatin decreased NCX1 mRNA. This effect was mediated by inhibition of HMG-CoA reductase by fluvastatin, leading to depletion of geranylgeranyl pirophosphate, which inhibited small GTP ases, especially RhoB. Therefore we concluded that RhoB was involved in NCX mRNA expression.
(2) We fond that lisophosphatidylcholine (LPC) increased NCX1 mRNA and protein expression. Therefore we investigated the mechanism of LPC increasing NCX1 expression. An inhibitor of geranylgeranyltransferase inhibited the effect of LPC on NCX1 expression. We propose that LPC may increase NCX1 expression by activating RhoB by accelerating the activity of geranylgeranyltransferase to prenylate RhoB.
(3) It had been known that reactive oxygen species increase cardiac NCX current, but its mechanism was unknown. We found that H_2O_2 increased NCX1 current in guinea pig cardiac ventricular cells. We investigated the mechanism of H_20_2 increasing NCX1 current in the ventricular cells of the guinea pig. The effect of H_20_2 was inhibited by a OH scavenger, edaravone; a Gi/o inhibitor, pertussion toxin; and MEK inhibitor U0126. The effect of a low concentration of H_2O_2 on NCX1 current was inhibited by PI3 kinase inhibitor, vormannin; and Na^+/H^+ exchanger inhibitor, cariporide. The effect of a high concentration of H_2O_2 was inhibited by Src kinase inhibitor, PP2. However, we could not detect tyrosin phosphorylation of NCX1 by H_2O_2. These result indicated that NCX1 function was enhanced by H_2O_2 converting to OH, activating Gi/o, and MAP kinase. Then a low concentration of OH activate PI3 kinase and Na^+/H^+ exchanger and activate NCX1. A high concentration of OH activated Src kinase and activate NCX1 indirectly.
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