Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure.
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.
Nakamura
Tomoe Y
TY
Department of Molecular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Iwata
Yuko
Y
Arai
Yuji
Y
Komamura
Kazuo
K
Wakabayashi
Shigeo
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048430:Cell Shape; D003593:Cytoplasm / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D000099211:Phospholamban
D019703:Calcineurin; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D027682:Cation Transport Proteins; D006146:Guanidines; D006655:Histone Deacetylases; D050778:NFATC Transcription Factors; D012964:Sodium; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D000099211:Phospholamban; C490998:SLC9A1 protein, human; C093373:cariporide; C498618:Hdac5 protein, mouse