Cardiomyocyte d-dopachrome tautomerase protects against heart failure
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
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
View: Text | PDF
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

×

Figure 8

Effects of cardiomyocyte DDT deletion on myocardial fibrosis after pressure overload.

Options: View larger image (or click on image) Download as PowerPoint
Effects of cardiomyocyte DDT deletion on myocardial fibrosis after press...
(A) Representative trichrome-stained sections of the left ventricle in CON and cKO mice 7 weeks after TAC or sham surgery. Lower images are original magnification ×10 of the myocardium in the area contained within the black box on the cross sections. (B and C) Connective tissue growth factor (Ctgf) and collagen type I α1 (Col1a1) expression in DDT-cKO mice 1 and 7 weeks after TAC. Left graphs in B and C quantify the percentage of fibrosis at 1 and 7 weeks after surgery. Middle and right graphs quantify LV Ctgf and Col1a1 mRNA transcripts, respectively, at 1 and 7 weeks after surgery. These data are shown as mean ± SEM; n = 4–7 mice per group. (D) The effects of rDDT treatment on TGF-β–induced Smad-2 phosphorylation in WT cardiac fibroblasts. Fibroblasts were isolated from WT mice hearts and incubated with or without TGF-β (1 ng/mL) for 1 hour and then treated with or without DDT (400 ng/mL) for 2 hours before cell lysis and immunoblotting. Graph shows the ratio of phosphorylated Smad-2 to total Smad-2. (E) The effects of rDDT treatment on TGF-β–induced Smad-2 phosphorylation in CD74-KO cardiac fibroblast. Fibroblasts were isolated from CD74–global KO mice hearts and incubated with or without TGF-β (1 ng/mL) for 1 hour and then treated with or without DDT (400 ng/mL) for 2 hours before cell lysis and immunoblotting. Graph shows the ratio of phosphorylated Smad-2 to total Smad-2. Data are shown as mean ± SEM; n = 3 independent studies. Significance determined by 1-way ANOVA with Tukey’s multiple-comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001 indicated by brackets.