{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:31:42Z","timestamp":1792168302127,"version":"4.4.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2008,10,10]]},"abstract":"<jats:p>\n            Activation of the sarcolemmal Na\n            <jats:sup>+<\/jats:sup>\n            \/H\n            <jats:sup>+<\/jats:sup>\n            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\n            <jats:sup>+<\/jats:sup>\n            concentrations were higher under both conditions. In addition, both diastolic and systolic Ca\n            <jats:sup>2+<\/jats:sup>\n            levels were increased as a consequence of Na\n            <jats:sup>+<\/jats:sup>\n            -induced Ca\n            <jats:sup>2+<\/jats:sup>\n            overload; this was accompanied by enhanced sarcoplasmic reticulum Ca\n            <jats:sup>2+<\/jats:sup>\n            loading via Ca\n            <jats:sup>2+<\/jats:sup>\n            \/calmodulin-dependent protein kinase (CaMK)II-dependent phosphorylation of phospholamban. Negative force\u2013frequency dependence was observed with preservation of high Ca\n            <jats:sup>2+<\/jats:sup>\n            , suggesting a decrease in myofibril Ca\n            <jats:sup>2+<\/jats:sup>\n            sensitivity. Furthermore, the Ca\n            <jats:sup>2+<\/jats:sup>\n            -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\n            <jats:sup>+<\/jats:sup>\n            \/H\n            <jats:sup>+<\/jats:sup>\n            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\u2013histone deacetylase pathway.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.175141","type":"journal-article","created":{"date-parts":[[2008,9,6]],"date-time":"2008-09-06T01:07:01Z","timestamp":1220663221000},"page":"891-899","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":175,"title":["Activation of Na\n            <sup>+<\/sup>\n            \/H\n            <sup>+<\/sup>\n            Exchanger 1 Is Sufficient to Generate Ca\n            <sup>2+<\/sup>\n            Signals That Induce Cardiac Hypertrophy and Heart Failure"],"prefix":"10.1161","volume":"103","author":[{"given":"Tomoe Y.","family":"Nakamura","sequence":"first","affiliation":[{"name":"From the Departments of Molecular Physiology (T.Y.N., Y.I., S.W.), Bioscience (Y.A.), and Cardiovascular Dynamics (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Iwata","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (T.Y.N., Y.I., S.W.), Bioscience (Y.A.), and Cardiovascular Dynamics (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Arai","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (T.Y.N., Y.I., S.W.), Bioscience (Y.A.), and Cardiovascular Dynamics (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Komamura","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (T.Y.N., Y.I., S.W.), Bioscience (Y.A.), and Cardiovascular Dynamics (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Wakabayashi","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (T.Y.N., Y.I., S.W.), Bioscience (Y.A.), and Cardiovascular Dynamics (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00841-6"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.85.9.777"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)01693-5"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.105.542209"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000014966.97486.c0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.77.6.1192"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36888-6"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9715472"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0360004"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100296200"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.012940"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1983"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00699-2"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27438"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.88.4.376"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1388-9842(02)00016-8"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/157016106775203117"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2006.05.016"},{"key":"e_1_3_3_19_2","first-page":"H1246","volume":"273","year":"1997","unstructured":"Maier LS, Pieske B, Allen DG. 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