Cardiomyocyte d-dopachrome tautomerase protects against heart failure
Yina Ma, … , Richard Bucala, Lawrence H. Young
Yina Ma, … , Richard Bucala, Lawrence H. Young
Published September 5, 2019
Citation Information: JCI Insight. 2019;4(17):e128900. https://doi.org/10.1172/jci.insight.128900.
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Research Article Cardiology

Cardiomyocyte d-dopachrome tautomerase protects against heart failure

Abstract

The mechanisms contributing to heart failure remain incompletely understood. d-dopachrome tautomerase (DDT) is a member of the macrophage migration inhibitory factor family of cytokines and is highly expressed in cardiomyocytes. This study examined the role of cardiomyocyte DDT in the setting of heart failure. Patients with advanced heart failure undergoing transplantation demonstrated decreased cardiac DDT expression. To understand the effect of loss of cardiac DDT in experimental heart failure, cardiomyocyte-specific DDT-KO (DDT-cKO) and littermate control mice underwent surgical transverse aortic constriction (TAC) to induce cardiac pressure overload. DDT-cKO mice developed more rapid cardiac contractile dysfunction, greater cardiac dilatation, and pulmonary edema after TAC. Cardiomyocytes from DDT-cKO mice after TAC had impaired contractility, calcium transients, and reduced expression of the sarcoplasmic reticulum calcium ATPase. The DDT-cKO hearts also exhibited diminished angiogenesis with reduced capillary density and lower VEGF-A expression after TAC. In pharmacological studies, recombinant DDT (rDDT) activated endothelial cell ERK1/2 and Akt signaling and had proangiogenic effects in vitro. The DDT-cKO hearts also demonstrated more interstitial fibrosis with enhanced collagen and connective tissue growth factor expression after TAC. In cardiac fibroblasts, rDDT had an antifibrotic action by inhibiting TGF-β–induced Smad-2 activation. Thus, endogenous cardiomyocyte DDT has pleiotropic actions that are protective against heart failure.

Authors

Yina Ma, Kevin N. Su, Daniel Pfau, Veena S. Rao, Xiaohong Wu, Xiaoyue Hu, Lin Leng, Xin Du, Marta Piecychna, Kenneth Bedi, Stuart G. Campbell, Anne Eichmann, Jeffrey M. Testani, Kenneth B. Margulies, Richard Bucala, Lawrence H. Young

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Figure 9

Plasma DDT and MIF concentrations in healthy individuals and patients with heart failure.

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Plasma DDT and MIF concentrations in healthy individuals and patients wi...
(A) Plasma DDT and MIF concentrations were measured by specific ELISA in healthy controls (Con, n = 43), heart failure with preserved ejection fraction (HFpEF, n = 41), and heart failure with reduced ejection fraction (HFrEF, n = 99). In the heart failure groups, plasma was measured following intensive diuretic therapy before discharge from the hospital. Control plasma was obtained from volunteer blood donors at our clinical research center. Data are shown as mean ± SEM. Significance determined by 1-way ANOVA with Tukey’s multiple-comparisons test. *P < 0.05; ****P < 0.0001 compared with control. (B) Correlation between plasma DDT and MIF concentrations with LV ejection fraction (EF) in heart failure patients (n = 140). (C) Correlation between plasma DDT and MIF concentrations with log brain natriuretic peptide level in patients with heart failure (n = 140). Pearson’s correlation was used for statistical comparison. (D) Kaplan-Meier survival curve comparing patients with heart failure (n = 140) with high and low DDT and MIF plasma concentrations. The median plasma concentrations of DDT (135 ng/mL) and MIF (7.05 ng/mL) were used to divide high versus low DDT and MIF groups. Log-rank test was used for statistical comparison.