Na⁺/H⁺交換輸送体の活性化は心肥大・心不全を引き起こす:細胞内イオン代謝と分子機構の解析

抄録

The sarcolemmal Na⁺/H⁺ exchanger1 (NHE1) is a primary mechanism for acid extrusion and a major Na⁺-influx pathway in myocardium. Recent evidence suggests that NHE1 activation is involved in cardiac hypertrophy and heart failure (HF). However, whether NHE1 activation alone is sufficient to induce detrimental effects or what molecular pathways are involved in pathogenesis remains unknown. To directly answer these questions, we generated cardiac-specific transgenic (Tg) mice overexpressing a constitutively-active form of human NHE1 (delta 637-656). We found that Tg hearts developed hypertrophy and HF in vivo, with activation of CaMKII and p38 MAPK. In isolated myocytes, intracellular pH, Na⁺ and Ca²⁺ concentrations were significantly elevated in Tg group, accompanied by enhanced SR Ca²⁺-loading via CaMKII-dependent phosphorylation of phospholamban. Furthermore, NHE1-overexpression induced translocation of HDAC4 and NFATc, fully to the cytoplasm but partially to the nucleous, respectively in cultured neonatal myocytes, suggesting that NHE1 activation can drive the Ca²⁺-dependent prohypertrophic pathway CaMKII-HDAC and partially calcineurin-NFAT signals. All NHE1-induced effects observed in vivo and in vitro were largely prevented by the specific inhibitor cariporide. Taken together, these data indicate that NHE1 activation, which induces an elevation of intracellular Na⁺ followed by altered Ca²⁺-handling, is sufficient to initiate cardiac hypertrophy and HF through mainly activation of the CaMKII-HDAC pathway. [J Physiol Sci. 2008;58 Suppl:S59]