{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T21:48:33Z","timestamp":1767908913815,"version":"3.49.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,9,8]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              The Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the \u03b2 isoform of the calcineurin catalytic A-subunit (CaNA\u03b2) is required for induction of pathological myocyte hypertrophy, despite calcineurin A\u03b1 expression in the same cells. It is unclear how the pleiotropic second messenger Ca\n              <jats:sup>2+<\/jats:sup>\n              drives excitation\u2013contraction coupling while not stimulating hypertrophy by calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectivity in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New F\u00f6rster resonance energy transfer reporters were used to assay Ca\n              <jats:sup>2+<\/jats:sup>\n              and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus\u2013mediated gene delivery in the mouse were used to study calcineurin signaling after transverse aortic constriction in vivo.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              CIP4 (Cdc42-interacting protein 4)\/TRIP10 (thyroid hormone receptor interactor 10) was identified as a new polyproline domain-dependent scaffold for CaNA\u03b22 by yeast 2-hybrid screen. Cardiac myocyte\u2013specific\n              <jats:italic>CIP4<\/jats:italic>\n              gene deletion in mice attenuated pressure overload\u2013induced pathological cardiac remodeling and heart failure. Blockade of CaNA\u03b2 polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes; disruption of anchoring in vivo using an adeno-associated virus gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell F\u00f6rster resonance energy transfer biosensor imaging of cultured myocytes revealed that Ca\n              <jats:sup>2+<\/jats:sup>\n              levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca\n              <jats:sup>2+<\/jats:sup>\n              levels and calcineurin activity detected by nonlocalized F\u00f6rster resonance energy transfer sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca\n              <jats:sup>2+<\/jats:sup>\n              and calcineurin signal transduction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              These results support a structural model for Ca\n              <jats:sup>2+<\/jats:sup>\n              and CaNA\u03b2 compartmentation in cells based on an isoform-specific mechanism for calcineurin protein\u2013protein interaction and localization. This mechanism provides an explanation for the specific role of CaNA\u03b2 in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNA\u03b2 polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNA\u03b2-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further preclinical investigation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044893","type":"journal-article","created":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T09:02:22Z","timestamp":1593680542000},"page":"948-962","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Calcineurin A\u03b2\u2013Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy"],"prefix":"10.1161","volume":"142","author":[{"given":"Xiaofeng","family":"Li","sequence":"first","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinliang","family":"Li","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."},{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliana C.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Froese","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.F., V.O.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine L.","family":"Passariello","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Henshaw","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Rusconi","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. 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Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)."},{"name":"Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viacheslav O.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.F., V.O.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-6953","authenticated-orcid":true,"given":"Michael S.","family":"Kapiloff","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. 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