{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:10:17Z","timestamp":1790172617919,"version":"4.1.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"27","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,7]]},"abstract":"<jats:p>\n                    Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    fluxes significantly impact on cardiac output and facilitate the development of arrhythmias. Using cardiomyocytes from spontaneously hypertensive rats (SHRs), we demonstrate that an increase in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release through inositol 1,4,5-trisphosphate receptors (InsP\n                    <jats:sub>3<\/jats:sub>\n                    Rs) contributes to the larger excitation contraction coupling (ECC)-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECC-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients and contraction elicited by InsP\n                    <jats:sub>3<\/jats:sub>\n                    or endothelin-1 (ET-1). Responsible for this is an increase in InsP\n                    <jats:sub>3<\/jats:sub>\n                    R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release through InsP\n                    <jats:sub>3<\/jats:sub>\n                    Rs served to sensitize RyRs, thereby increasing diastolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels, the incidence of extra-systolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients, and the induction of ECC-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    elevations. Unlike the increase in InsP\n                    <jats:sub>3<\/jats:sub>\n                    R expression and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient amplitude in the cytosol, InsP\n                    <jats:sub>3<\/jats:sub>\n                    R expression and ECC-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients in the nucleus were not altered during hypertrophy. Elevated InsP\n                    <jats:sub>3<\/jats:sub>\n                    R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. Our data establish that increased InsP\n                    <jats:sub>3<\/jats:sub>\n                    R expression is a general mechanism that underlies remodeling of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0905485106","type":"journal-article","created":{"date-parts":[[2009,6,23]],"date-time":"2009-06-23T23:04:45Z","timestamp":1245798285000},"page":"11406-11411","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":118,"title":["Increased InsP\n                    <sub>3<\/sub>\n                    Rs in the junctional sarcoplasmic reticulum augment Ca\n                    <sup>2+<\/sup>\n                    transients and arrhythmias associated with cardiac hypertrophy"],"prefix":"10.1073","volume":"106","author":[{"given":"Dagmar","family":"Harzheim","sequence":"first","affiliation":[{"name":"Department of Molecular Signaling, Babraham Institute, Cambridge, CB22 3AT, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehregan","family":"Movassagh","sequence":"additional","affiliation":[{"name":"Addenbrooke's Centre for Clinical Investigation, Cambridge, CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.-Y.","family":"Foo","sequence":"additional","affiliation":[{"name":"Addenbrooke's Centre for Clinical Investigation, Cambridge, CB2 0QQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Medicine I, University of Wuerzburg, 97080 Wuerzburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aslam","family":"Tashfeen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of St. Andrews, St. Andrews, KY16 9ST, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J.","family":"Conway","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Oxford, Oxford, OX1 3TA, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin D.","family":"Bootman","sequence":"additional","affiliation":[{"name":"Department of Molecular Signaling, Babraham Institute, Cambridge, CB22 3AT, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Llewelyn","family":"Roderick","sequence":"additional","affiliation":[{"name":"Department of Molecular Signaling, Babraham Institute, Cambridge, CB22 3AT, United Kingdom;"},{"name":"Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,7,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1067\/mhj.2001.113218"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1983"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1155"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5313.800"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2004.042473"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.120.5.1137"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb04882.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.38.23961"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)00624-2"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013411"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000172556.05576.4c"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.058529"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03073"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.05.014"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.02.005"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117739"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00926853"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(08)80035-1"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.4.424"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.84.12.1453"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01524-8"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1996.0288"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.4.H1348"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1159\/000095517"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01144-5"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.2174\/157016105774329390"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.021386"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.22.3979"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810799106"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050021"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-198205000-00013"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2007.05.004"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0905485106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:15:19Z","timestamp":1649787319000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0905485106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7,7]]},"references-count":33,"journal-issue":{"issue":"27","published-print":{"date-parts":[[2009,7,7]]}},"alternative-id":["10.1073\/pnas.0905485106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0905485106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,7,7]]},"assertion":[{"value":"2009-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-07-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}