{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:18:05Z","timestamp":1793017085682,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,1,17]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              The Na\n              <jats:sup>+<\/jats:sup>\n              \/K\n              <jats:sup>+<\/jats:sup>\n              ATPase (NKA) directly regulates intracellular Na\n              <jats:sup>+<\/jats:sup>\n              levels, which in turn indirectly regulates Ca\n              <jats:sup>2+<\/jats:sup>\n              levels by proximally controlling flux through the Na\n              <jats:sup>+<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              exchanger (NCX1). Elevated Na\n              <jats:sup>+<\/jats:sup>\n              levels have been reported during heart failure, which permits some degree of reverse-mode Ca\n              <jats:sup>2+<\/jats:sup>\n              entry through NCX1, as well as less efficient Ca\n              <jats:sup>2+<\/jats:sup>\n              clearance.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              To determine whether maintaining lower intracellular Na\n              <jats:sup>+<\/jats:sup>\n              levels by NKA overexpression in the heart would enhance forward-mode Ca\n              <jats:sup>2+<\/jats:sup>\n              clearance and prevent reverse-mode Ca\n              <jats:sup>2+<\/jats:sup>\n              entry through NCX1 to protect the heart.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Cardiac-specific transgenic mice overexpressing either NKA-\u03b11 or NKA-\u03b12 were generated and subjected to pressure overload hypertrophic stimulation. We found that although increased expression of NKA-\u03b11 had no protective effect, overexpression of NKA-\u03b12 significantly decreased cardiac hypertrophy after pressure overload in mice at 2, 10, and 16 weeks of stimulation. Remarkably, total NKA protein expression and activity were not altered in either of these 2 transgenic models because increased expression of one isoform led to a concomitant decrease in the other endogenous isoform. NKA-\u03b12 overexpression but not NKA-\u03b11 led to significantly faster removal of bulk Ca\n              <jats:sup>2+<\/jats:sup>\n              from the cytosol in a manner requiring NCX1 activity. Mechanistically, overexpressed NKA-\u03b12 showed greater affinity for Na\n              <jats:sup>+<\/jats:sup>\n              compared with NKA-\u03b11, leading to more efficient clearance of this ion. Furthermore, overexpression of NKA-\u03b12 but not NKA-\u03b11 was coupled to a decrease in phospholemman expression and phosphorylation, which would favor greater NKA activity, NCX1 activity, and Ca\n              <jats:sup>2+<\/jats:sup>\n              removal.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Our results suggest that the protective effect produced by increased expression of NKA-\u03b12 on the heart after pressure overload is due to more efficient Ca\n              <jats:sup>2+<\/jats:sup>\n              clearance because this isoform of NKA preferentially enhances NCX1 activity compared with NKA-\u03b11.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.114.302293","type":"journal-article","created":{"date-parts":[[2013,11,12]],"date-time":"2013-11-12T05:01:22Z","timestamp":1384232482000},"page":"249-256","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":66,"title":["Overexpression of the Na\n            <sup>+<\/sup>\n            \/K\n            <sup>+<\/sup>\n            ATPase \u03b12 But Not \u03b11 Isoform Attenuates Pathological Cardiac Hypertrophy and Remodeling"],"prefix":"10.1161","volume":"114","author":[{"given":"Robert N.","family":"Correll","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Eder","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Burr","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Despa","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Davis","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, OH (R.N.C., P.E., A.R.B., J.D., J.D.M.); Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.); Comprehensive Heart Failure Center, University of W\u00fcrzburg, W\u00fcrzburg, Germany (P.E.); and Department of Pharmacology, UC Davis, CA (S.D., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.CPJ06001X"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00735-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000023042.50192.f4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.05.001"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000016701.85760.97"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00809-X"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.23.2545"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(00)00730-0"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2004.12.012"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.108.175141"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2011.11.003"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-010-0136-x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410737200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2326638"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2010.06.006"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.01.014"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0146-2806(96)80001-6"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.16.2105"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000181172.27931.c3"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-184903"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80349-4"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.006"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs213"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.030536"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000109415.17511.18"},{"key":"e_1_3_4_27_2","first-page":"976","article-title":"Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents.","volume":"119","author":"Wu X","year":"2009","unstructured":"Wu X, Chang B, Blair NS, Sargent M, York AJ, Robbins J, Shull GE, Molkentin JD. 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