Universität zu Köln

Qi, Dake, Atsina, Kwame, Qu, Lintao, Hu, Xiaoyue, Wu, Xiaohong, Xu, Bin, Piecychna, Marta, Leng, Lin ORCID: 0000-0002-0605-358X, Fingerle-Rowson, Guenter, Zhang, Jiasheng, Bucala, Richard and Young, Lawrence H. (2014). The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. J. Clin. Invest., 124 (8). S. 3540 - 3551. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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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 Ddt(fl/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 DOT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Qi, Dake UNSPECIFIED UNSPECIFIED UNSPECIFIED Atsina, Kwame UNSPECIFIED UNSPECIFIED UNSPECIFIED Qu, Lintao UNSPECIFIED UNSPECIFIED UNSPECIFIED Hu, Xiaoyue UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Xiaohong UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Bin UNSPECIFIED UNSPECIFIED UNSPECIFIED Piecychna, Marta UNSPECIFIED UNSPECIFIED UNSPECIFIED Leng, Lin UNSPECIFIED orcid.org/0000-0002-0605-358X UNSPECIFIED Fingerle-Rowson, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Jiasheng UNSPECIFIED UNSPECIFIED UNSPECIFIED Bucala, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Young, Lawrence H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-432882
DOI:	10.1172/JCI73061
Journal or Publication Title:	J. Clin. Invest.
Volume:	124
Number:	8
Page Range:	S. 3540 - 3551
Date:	2014
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MIGRATION-INHIBITORY FACTOR; FATTY-ACID OXIDATION; FACTOR MIF; REPERFUSION INJURY; KINASE KINASE; FUNCTIONAL RECOVERY; RECEPTOR COMPLEX; GLUCOSE-UPTAKE; ACTIVATION; AMPK Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43288