{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:30:15Z","timestamp":1790188215541,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,1,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">CDNF (cerebral dopamine neurotrophic factor) belongs to a new family of neurotrophic factors that exert systemic beneficial effects beyond the brain. Little is known about the role of CDNF in the cardiac context. Herein we investigated the effects of CDNF under endoplasmic reticulum\u2010stress conditions using cardiomyocytes (humans and mice) and isolated rat hearts, as well as in rats subjected to ischemia\/reperfusion (I\/R).<\/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\">We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I\/R. Recombinant CDNF (exoCDNF) protected human and mouse cardiomyocytes against endoplasmic reticulum stress and restored the calcium transient. In isolated hearts subjected to I\/R, exoCDNF avoided mitochondrial impairment and reduced the infarct area to 19% when administered before ischemia and to 25% when administered at the beginning of reperfusion, compared with an infarct area of 42% in the untreated I\/R group. This protection was completely abrogated by AKT (protein kinase B) inhibitor. Heptapeptides containing the KDEL sequence, which binds to the KDEL\u2010R (KDEL receptor), abolished exoCDNF beneficial effects, suggesting the participation of KDEL\u2010R in this cardioprotection. CDNF administered intraperitoneally to rats decreased the infarct area in an in vivo model of I\/R (from an infarct area of \u224844% in the I\/R group to an infarct area of \u224827%). Moreover, a shorter version of CDNF, which lacks the last 4 residues (CDNF\u2010\u0394KTEL) and thus allows CDNF binding to KDEL\u2010R, presented no cardioprotective activity in isolated hearts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This is the first study to propose CDNF as a new cardiomyokine that induces cardioprotection via KDEL receptor binding and PI3K\/AKT activation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.120.019685","type":"journal-article","created":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T08:03:03Z","timestamp":1609228983000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["New Cardiomyokine Reduces Myocardial Ischemia\/Reperfusion Injury by PI3K\u2010AKT Pathway Via a Putative KDEL\u2010Receptor Binding"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1168-8926","authenticated-orcid":false,"given":"Leonardo","family":"Maciel","sequence":"first","affiliation":[{"name":"Institute of Biophysics Carlos Chagas Filho Federal University of Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8104-9476","authenticated-orcid":false,"given":"Dahienne Ferreira","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry Leopoldo de Meis Rio de Janeiro Federal, University of Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-010X","authenticated-orcid":false,"given":"Fernanda","family":"Mesquita","sequence":"additional","affiliation":[{"name":"Institute of Biophysics Carlos Chagas Filho Federal University of Rio de Janeiro 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