Key result
Cardiomyocyte-specific deletion of d-dopachrome tautomerase in mice accelerated heart failure after pressure overload, and failing human hearts demonstrated significantly reduced DDT expression.
Why the study?
The mechanisms contributing to heart failure remain incompletely understood, prompting examination of the role of cardiomyocyte d-dopachrome tautomerase (DDT).
Does cardiomyocyte d-dopachrome tautomerase (DDT) protect against heart failure progression and adverse remodeling during pressure overload?
Does cardiomyocyte d-dopachrome tautomerase (DDT) protect against heart failure progression and adverse remodeling during pressure overload?
Endogenous cardiomyocyte d-dopachrome tautomerase (DDT) exerts pleiotropic protective effects against pressure overload-induced heart failure by preserving contractility, promoting angiogenesis, and limiting fibrosis.
Supports protective role of cardiomyocyte DDT in pressure overload; leaves open whether DDT modulation alters human HF outcomes.
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.
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Ma et al. (2019) studied Heart failure. d-dopachrome tautomerase (DDT) deficiency vs. Normal DDT expression (Wild-type or healthy controls) was evaluated on Development of cardiac contractile dysfunction and heart failure. Cardiomyocyte-specific deletion of d-dopachrome tautomerase in mice accelerated heart failure after pressure overload, and failing human hearts demonstrated significantly reduced DDT expression.
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