{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:26:12Z","timestamp":1791919572543,"version":"4.3.4"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"17","funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL128069"],"award-info":[{"award-number":["R01HL128069"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["RO1 AR049610"],"award-info":[{"award-number":["RO1 AR049610"]}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL089847"],"award-info":[{"award-number":["HL089847"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["HL105993"],"award-info":[{"award-number":["HL105993"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,5]]},"abstract":"<jats:p>The mechanisms contributing to heart failure remain incompletely understood. d-dopachrome tautomerase (DDT) is a member of the macrophage migration inhibitory factor family of cytokines and is highly expressed in cardiomyocytes. This study examined the role of cardiomyocyte DDT in the setting of heart failure. Patients with advanced heart failure undergoing transplantation demonstrated decreased cardiac DDT expression. To understand the effect of loss of cardiac DDT in experimental heart failure, cardiomyocyte-specific DDT-KO (DDT-cKO) and littermate control mice underwent surgical transverse aortic constriction (TAC) to induce cardiac pressure overload. DDT-cKO mice developed more rapid cardiac contractile dysfunction, greater cardiac dilatation, and pulmonary edema after TAC. Cardiomyocytes from DDT-cKO mice after TAC had impaired contractility, calcium transients, and reduced expression of the sarcoplasmic reticulum calcium ATPase. The DDT-cKO hearts also exhibited diminished angiogenesis with reduced capillary density and lower VEGF-A expression after TAC. In pharmacological studies, recombinant DDT (rDDT) activated endothelial cell ERK1\/2 and Akt signaling and had proangiogenic effects in vitro. The DDT-cKO hearts also demonstrated more interstitial fibrosis with enhanced collagen and connective tissue growth factor expression after TAC. In cardiac fibroblasts, rDDT had an antifibrotic action by inhibiting TGF-\u03b2\u2013induced Smad-2 activation. Thus, endogenous cardiomyocyte DDT has pleiotropic actions that are protective against heart failure.<\/jats:p>","DOI":"10.1172\/jci.insight.128900","type":"journal-article","created":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T11:01:02Z","timestamp":1567594862000},"source":"Crossref","is-referenced-by-count":26,"title":["Cardiomyocyte d-dopachrome tautomerase protects against heart failure"],"prefix":"10.1172","volume":"4","author":[{"given":"Yina","family":"Ma","sequence":"first","affiliation":[{"name":"Yale Cardiovascular Research Center,"},{"name":"Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin N.","family":"Su","sequence":"additional","affiliation":[{"name":"Yale Cardiovascular Research Center,"},{"name":"Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, 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