{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:00:29Z","timestamp":1791547229570,"version":"4.3.4"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2015,3,24]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Thioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing mitochondrial reactive oxygen species generation and by inhibiting apoptosis stress kinase-1 (ASK1)\u2013dependent apoptotic signaling. To date, the role of the mitochondrial Trx2 system in heart failure pathogenesis has not been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>Western blot and histological analysis revealed that Trx2 protein expression levels were reduced in hearts from patients with dilated cardiomyopathy, with a concomitant increase in ASK1 phosphorylation\/activity. Cardiac-specific Trx2 knockout mice develop spontaneous dilated cardiomyopathy at 1 month of age with increased heart size, reduced ventricular wall thickness, and a progressive decline in left ventricular contractile function, resulting in mortality due to heart failure by \u22484 months of age. The progressive decline in cardiac function observed in cardiac-specific Trx2 knockout mice was accompanied by the disruption of mitochondrial ultrastructure, mitochondrial membrane depolarization, increased mitochondrial reactive oxygen species generation, and reduced ATP production, correlating with increased ASK1 signaling and increased cardiomyocyte apoptosis. Chronic administration of a highly selective ASK1 inhibitor improved cardiac phenotype and reduced maladaptive left ventricular remodeling with significant reductions in oxidative stress, apoptosis, fibrosis, and cardiac failure. Cellular data from Trx2-deficient cardiomyocytes demonstrated that ASK1 inhibition reduced apoptosis and reduced mitochondrial reactive oxygen species generation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Our data support an essential role for mitochondrial Trx2 in preserving cardiac function by suppressing mitochondrial reactive oxygen species production and ASK1-dependent apoptosis. Inhibition of ASK1 represents a promising therapeutic strategy for the treatment of dilated cardiomyopathy and heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.114.012725","type":"journal-article","created":{"date-parts":[[2015,1,27]],"date-time":"2015-01-27T21:57:47Z","timestamp":1422395867000},"page":"1082-1097","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":162,"title":["Thioredoxin-2 Inhibits Mitochondrial Reactive Oxygen Species Generation and Apoptosis Stress Kinase-1 Activity to Maintain Cardiac Function"],"prefix":"10.1161","volume":"131","author":[{"given":"Qunhua","family":"Huang","sequence":"first","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanjiao Jenny","family":"Zhou","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ford","family":"Hinojosa-Kirschenbaum","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peidong","family":"Fan","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Yao","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz","family":"Belardinelli","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Tellides","sequence":"additional","affiliation":[{"name":"From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); 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