Activation of the sarcolemmal
Na(+)/H(+) exchanger (NHE)1 is increasingly documented as a process involved in
cardiac hypertrophy and
heart failure. However, whether NHE1 activation alone is sufficient to induce such remodeling remains unknown. We generated transgenic mice that overexpress a human NHE1 with high activity in hearts. The hearts of these mice developed
cardiac hypertrophy, contractile dysfunction, and
heart failure. In isolated transgenic myocytes, intracellular pH was elevated in
Hepes buffer but not in physiological
bicarbonate buffer, yet intracellular Na(+) concentrations were higher under both conditions. In addition, both diastolic and systolic Ca(2+) levels were increased as a consequence of Na(+)-induced Ca(2+) overload; this was accompanied by enhanced sarcoplasmic reticulum Ca(2+) loading via
Ca(2+)/calmodulin-dependent protein kinase (CaMK)II-dependent phosphorylation of
phospholamban. Negative force-frequency dependence was observed with preservation of high Ca(2+), suggesting a decrease in myofibril Ca(2+) sensitivity. Furthermore, the Ca(2+)-dependent prohypertrophic molecules
calcineurin and
CaMKII were highly activated in transgenic hearts. These effects observed in vivo and in vitro were largely prevented by the NHE1 inhibitor
cariporide. Interestingly, overexpression of NHE1 in neonatal rat ventricular myocytes induced
cariporide-sensitive nuclear translocation of NFAT (nuclear factor of activated T cells) and nuclear export of
histone deacetylase 4, suggesting that increased Na(+)/H(+) exchange activity can alter
hypertrophy-associated gene expression. However, in transgenic myocytes, contrary to exclusive translocation of
histone deacetylase 4, NFAT only partially translocated to nucleus, possibly because of marked activation of p38, a negative regulator of NFAT signaling. We conclude that activation of NHE1 is sufficient to initiate
cardiac hypertrophy and
heart failure mainly through activation of
CaMKII-
histone deacetylase pathway.