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
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
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Research Article Cardiology

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

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

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Figure 5

Differential AMPK activation and cardiac injury after ischemia inMif–/–andCd74–/–hearts.

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Differential AMPK activation and cardiac injury after ischemia inMif–/–...
(A) Hearts from WT, Mif–/–, and Cd74–/– mice were perfused ex vivo at normal flow for 30 minutes and then subjected to ischemia (15 minutes) with or without subsequent reperfusion (30 minutes). Control hearts were perfused at normal flow (4 ml/min) for 75 minutes. Heart homogenates were prepared after ischemia without reperfusion (IS) or control perfusion and immunoblotted with phospho-AMPK (Thr172) and total AMPK antibodies. (B) LVDP•HR index during the in vitro perfusion protocols. (C) Mice underwent ligation of the left coronary artery (or control sham ligation) for 20 minutes with or without subsequent reperfusion for 3 hours. Phospho-AMPK (Thr172) and total AMPK were assessed in heart homogenates after ischemia without reperfusion. (D) Myocardial necrosis, determined by TTC and Evans blue staining and expressed as a percentage of the ischemic “risk area” served by the occluded artery. (E) Myocardial necrosis was also assessed by measurement of serum troponin I after ischemia-reperfusion (I-R) or sham surgery. Data are mean ± SEM, n = 5–6 per group. *P < 0.05 vs. respective control or as indicated by brackets.