The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury

Dake Qi, Kwame Atsina, Lintao Qu, Xiaoyue Hu, Xiaohong Wu, Bin Xu, Marta Piecychna, Lin Leng, Günter Fingerle-Rowson, Jiasheng Zhang, Richard Bucala, Lawrence H. Young

Research output: Contribution to journalArticle

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 Ddt fl/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.

Original languageEnglish (US)
Pages (from-to)3540-3550
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Qi, D., Atsina, K., Qu, L., Hu, X., Wu, X., Xu, B., Piecychna, M., Leng, L., Fingerle-Rowson, G., Zhang, J., Bucala, R., & Young, L. H. (2014). The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. Journal of Clinical Investigation, 124(8), 3540-3550. https://doi.org/10.1172/JCI73061