{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T08:36:02Z","timestamp":1793349362474,"version":"4.5.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2010,9,3]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Inositol 1,4,5-trisphosphate (IP\n              <jats:sub>3<\/jats:sub>\n              ) is a second messenger that regulates intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              release through IP\n              <jats:sub>3<\/jats:sub>\n              receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein\u2013coupled receptor (GPCR) signaling events lead to IP\n              <jats:sub>3<\/jats:sub>\n              liberation, although its importance in transducing the hypertrophic response has not been established in vivo.\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              Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP\n              <jats:sub>3<\/jats:sub>\n              receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation.\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              Overexpression of the mouse type-2 IP\n              <jats:sub>3<\/jats:sub>\n              receptor (IP\n              <jats:sub>3<\/jats:sub>\n              R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca\n              <jats:sup>2+<\/jats:sup>\n              transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP\n              <jats:sub>3<\/jats:sub>\n              R2 overexpression failed to augment\/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to G\u03b1q overexpression, and\/or in response to exercise stimulation. To inhibit IP\n              <jats:sub>3<\/jats:sub>\n              signaling in vivo, we generated transgenic mice expressing an IP\n              <jats:sub>3<\/jats:sub>\n              chelating protein (IP\n              <jats:sub>3<\/jats:sub>\n              -sponge). IP\n              <jats:sub>3<\/jats:sub>\n              -sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP\n              <jats:sub>3<\/jats:sub>\n              R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-A\u03b2\u2013null background.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusion:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              These results indicate that IP\n              <jats:sub>3<\/jats:sub>\n              -mediated Ca\n              <jats:sup>2+<\/jats:sup>\n              release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.110.220038","type":"journal-article","created":{"date-parts":[[2010,7,9]],"date-time":"2010-07-09T03:03:34Z","timestamp":1278644614000},"page":"659-666","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":171,"title":["The IP\n            <sub>3<\/sub>\n            Receptor Regulates Cardiac Hypertrophy in Response to Select Stimuli"],"prefix":"10.1161","volume":"107","author":[{"given":"Hiroyuki","family":"Nakayama","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Bodi","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjorie","family":"Maillet","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"DeSantiago","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy L.","family":"Domeier","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiko","family":"Mikoshiba","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N.","family":"Lorenz","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar A.","family":"Blatter","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (H.N., I.B., M.M., J.D.M.), Division of Molecular Cardiovascular Biology; and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children's Hospital Medical Center, Ohio; Department of Pharmacology (J.D., D.M.B.), University of California, Davis; Department of Molecular Biophysics and Physiology (T.L.D., L.A.B.), Rush University School of Medicine, Chicago, Ill; RIKEN Brain Science Institute, \u201cSORST-JST\u201d (K.M.), Saitama, Japan; 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