{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:08:26Z","timestamp":1791137306534,"version":"4.1.0"},"reference-count":81,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2013,3,12]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte\u2010specific constitutively active FoxO3 mutant (\n                      <jats:italic>caFoxO3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>flox<\/jats:italic>\n                      <\/jats:sup>\n                      ;\u03b1\n                      <jats:italic>MHC\u2010Mer\u2010Cre\u2010Mer<\/jats:italic>\n                      ). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2\/adenovirus E1B 19\u2010\n                      <jats:styled-content style=\"fixed-case\">kD<\/jats:styled-content>\n                      a interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the\n                      <jats:italic>caFoxO3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>flox<\/jats:italic>\n                      <\/jats:sup>\n                      ;\u03b1\n                      <jats:italic>MHC\u2010Mer\u2010Cre\u2010Mer<\/jats:italic>\n                      mice with Bnip3\u2010null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3\u2010driven activation of the ubiquitin\u2010proteasome system, we detected time\u2010dependent activation of the atrogenes program and sarcomere protein breakdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy\u2010lysosomal and ubiquitin\u2010proteasomal pathways to orchestrate cardiac muscle atrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.113.000016","type":"journal-article","created":{"date-parts":[[2013,5,24]],"date-time":"2013-05-24T12:49:31Z","timestamp":1369399771000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["Mechanical Unloading Activates FoxO3 to Trigger Bnip3\u2010Dependent Cardiomyocyte Atrophy"],"prefix":"10.1161","volume":"2","author":[{"given":"Dian J.","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Blagg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet L.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Gondalia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misook","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai\u2010Chun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Shelton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly A.","family":"Rothermel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Gillette","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Gerald 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