{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:59:53Z","timestamp":1790722793564,"version":"4.1.0"},"reference-count":50,"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":[[2012,7,6]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in\n              <jats:italic>NKX2.5<\/jats:italic>\n              have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the\n              <jats:italic>NKX2.5<\/jats:italic>\n              locus, as causative for lethal arrhythmias (\u201csudden cardiac death\u201d) that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and\/or factors acting in epistasis with Nkx2.5\/NKX2.5.\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 identify bone fide upstream genetic modifier(s) of Nkx2.5\/NKX2.5 function and to determine epistatic effects relevant to the manifestation of\n              <jats:italic>NKX2.5<\/jats:italic>\n              -dependent adult congenital heart disease.\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              A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in\n              <jats:italic>Nkx2.5<\/jats:italic>\n              <jats:sup>Cre\/+<\/jats:sup>\n              ;\n              <jats:italic>Prox1<\/jats:italic>\n              <jats:sup>loxP\/+<\/jats:sup>\n              animals versus\n              <jats:italic>Nkx2.5<\/jats:italic>\n              <jats:sup>Cre\/+<\/jats:sup>\n              controls. Anatomic studies, on a\n              <jats:italic>Cx40<\/jats:italic>\n              <jats:sup>EGFP<\/jats:sup>\n              background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in\n              <jats:italic>Nkx2.5<\/jats:italic>\n              <jats:sup>Cre\/+<\/jats:sup>\n              littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca\n              <jats:sup>2+<\/jats:sup>\n              handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress\n              <jats:italic>Nkx2.5<\/jats:italic>\n              via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.111.260695","type":"journal-article","created":{"date-parts":[[2012,5,30]],"date-time":"2012-05-30T05:39:27Z","timestamp":1338356367000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Epistatic Rescue of Nkx2.5 Adult Cardiac Conduction Disease Phenotypes by Prospero-Related Homeobox Protein 1 and HDAC3"],"prefix":"10.1161","volume":"111","author":[{"given":"Catherine A.","family":"Risebro","sequence":"first","affiliation":[{"name":"From the Institute of Child Health (C.A.R., L.K.P.), University College London, London, UK; Department of Physiology, Anatomy and Genetics (N.S., J.M.V., P.R.R.),University of Oxford, Oxford, UK; Department of Metabolism and Experimental Therapeutics (J.G., Z.Z.), Rayne Institute, University College London, London, UK; King's College London (J.C.), BHF Centre, St Thomas' Hospital, London, UK; Cardiovascular Medicine (J.Y., H.D.), University of Manchester, Manchester, UK; The Hatter Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa K.","family":"Petchey","sequence":"additional","affiliation":[{"name":"From the Institute of Child Health (C.A.R., L.K.P.), University College London, London, UK; Department of Physiology, Anatomy and Genetics (N.S., J.M.V., P.R.R.),University of Oxford, Oxford, UK; Department of Metabolism and Experimental Therapeutics (J.G., Z.Z.), Rayne Institute, University College London, London, UK; King's College London (J.C.), BHF Centre, St Thomas' Hospital, London, UK; Cardiovascular Medicine (J.Y., H.D.), University of Manchester, Manchester, UK; The Hatter Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Smart","sequence":"additional","affiliation":[{"name":"From the Institute of Child Health (C.A.R., L.K.P.), University College London, London, UK; Department of Physiology, Anatomy and Genetics (N.S., J.M.V., P.R.R.),University of Oxford, Oxford, UK; Department of Metabolism and Experimental Therapeutics (J.G., Z.Z.), Rayne Institute, University College London, London, UK; King's College London (J.C.), BHF Centre, St Thomas' Hospital, London, UK; Cardiovascular Medicine (J.Y., H.D.), University of Manchester, Manchester, UK; The Hatter Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Gomes","sequence":"additional","affiliation":[{"name":"From the Institute of Child Health (C.A.R., L.K.P.), University College London, London, UK; Department of Physiology, Anatomy and Genetics (N.S., J.M.V., P.R.R.),University of Oxford, Oxford, UK; Department of Metabolism and Experimental Therapeutics (J.G., Z.Z.), Rayne Institute, University College London, London, UK; King's College London (J.C.), BHF Centre, St Thomas' Hospital, London, UK; Cardiovascular Medicine (J.Y., H.D.), University of Manchester, Manchester, UK; The Hatter Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Clark","sequence":"additional","affiliation":[{"name":"From the Institute of Child Health (C.A.R., L.K.P.), University College London, London, UK; Department of Physiology, Anatomy and Genetics (N.S., J.M.V., P.R.R.),University of Oxford, Oxford, UK; Department of Metabolism and Experimental Therapeutics (J.G., Z.Z.), Rayne Institute, University College London, London, UK; King's College London (J.C.), BHF Centre, St Thomas' Hospital, London, UK; Cardiovascular Medicine (J.Y., H.D.), University of Manchester, Manchester, UK; The Hatter 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