title: The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury.
abstract: The cellular response to stress involves the recruitment and coordination of molecular signaling pathways that prevent cell death. D-dopachrome tautomerase (DDT) is an enzyme that lacks physiologic substrates in mammalian cells, but shares partial sequence and structural homology with macrophage migration inhibitory factor (MIF). Here, we observed that DDT is highly expressed in murine cardiomyocytes and secreted by the heart after ischemic stress. Antibody-dependent neutralization of secreted DDT exacerbated both ischemia-induced cardiac contractile dysfunction and necrosis. We generated cardiomyocyte-specific DDT knockout mice (Myh6-Cre Ddtfl/fl), which demonstrated normal baseline cardiac size and function, but had an impaired physiologic response to ischemia-reperfusion. Hearts from Myh6-Cre Ddtfl/fl mice exhibited more necrosis and LV contractile dysfunction than control hearts after coronary artery ligation and reperfusion. Furthermore, treatment with DDT protected isolated hearts against injury and contractile dysfunction after ischemia-reperfusion. The protective effect of DDT required activation of the metabolic stress enzyme AMP-activated protein kinase (AMPK), which was mediated by a CD74/CaMKK2-dependent mechanism. Together, our data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.
authors.forename: Dake
authors.initials: D
authors.lastname: Qi
authors.forename: Kwame
authors.initials: K
authors.lastname: Atsina
authors.forename: Lintao
authors.initials: L
authors.lastname: Qu
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Marta
authors.initials: M
authors.lastname: Piecychna
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase